Review
Biochemistry & Molecular Biology
Sripriya J. Raja, Bennett Van Houten
Summary: Base excision repair (BER) is a cellular process that removes damaged bases arising from various sources. Multiple proteins, including UV-damaged DNA binding protein (UV-DDB), play important roles in BER to efficiently resolve DNA damage. UV-DDB not only stimulates the activities of several DNA glycosylases but also assists chromatin decompaction, facilitating access of OGG1 to damaged DNA. This review summarizes the essential role of UV-DDB in BER as demonstrated through various approaches.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Biochemistry & Molecular Biology
Katja Apelt, Hannes Lans, Orlando D. Scharer, Martijn S. Luijsterburg
Summary: GG-NER utilizes the interplay between XPC and DDB2 as well as post-translational modifications to regulate the recognition and repair of DNA lesions in nucleosomes. The repair process leaves a mark on chromatin, enabling detection of DNA damage in nucleosomes.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Review
Oncology
Nawar Al Nasrallah, Benjamin M. Wiese, Catherine R. Sears
Summary: XPC is not only important in skin cancer, but also plays a protective role in non-dermatologic cancers. In addition to its involvement in GG-NER, XPC also participates in other DNA repair pathways, DNA damage response, and transcriptional regulation. XPC expression levels and polymorphisms may impact development and could serve as predictive and therapeutic biomarkers for non-dermatologic cancers.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Nikhil Jakhar, Akshay Prabhakant, Marimuthu Krishnan
Summary: UV radiation-induced DNA damages, particularly the cyclobutane pyrimidine dimer (CPD) lesions, have adverse effects on genome integrity and cellular function. Rad4/XPC protein is responsible for recognizing and repairing CPD lesions, but the molecular mechanism behind this process has been elusive. By using enhanced sampling and molecular dynamics simulations, this study investigates the mechanism and energetics of lesion recognition by Rad4/XPC. The findings shed light on the sequence of events and their potential coupling, providing important insights into understanding UV-related skin disorders and cancers and facilitating the development of novel therapeutic strategies.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Genetics & Heredity
Safiah Almushawwah, Mikhlid H. Almutairi, Abdullah M. Alamri, Abdelhabib Semlali
Summary: This study explored the association between four single nucleotide polymorphisms (SNPs) in XPA and XPC genes and cigarette smoking (CS) in the Saudi population. The results showed that SNP rs3176751 in XPA gene had a high-risk association with CS-induced diseases, while rs1800975 had a statistically significant low-risk association. In the XPC gene, SNP rs2607775 had a significant low-risk association, while rs2228000 and rs1870134 showed no association with CS.
Article
Biochemistry & Molecular Biology
Matthew A. Schaich, Brittani L. Schnable, Namrata Kumar, Vera Roginskaya, Rachel C. Jakielski, Roman Urban, Zhou Zhong, Neil M. Kad, Bennett Van Houten
Summary: Single-molecule characterization of protein-DNA dynamics provides detailed mechanistic insights into nuclear processes. A new method for rapidly generating single-molecule information using fluorescently tagged proteins isolated from human cells is described. The wide applicability of this technique is demonstrated on undamaged DNA and three forms of DNA damage, using seven native DNA repair proteins and two structural variants.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Sunbok Jang, Namrata Kumar, Mathew A. Schaich, Zhou Zhong, Barbara van Loon, Simon C. Watkins, Bennett Van Houten
Summary: This study discovered that UV-DDB has specific recognition for N-6-ethenoadenine and hypoxanthine, besides oxidized bases, and it stimulates AAG activity and helps with the release of AAG from abasic sites, facilitating the repair process.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Multidisciplinary Sciences
Charlotte Blessing, Katja Apelt, Diana van den Heuvel, Claudia Gonzalez-Leal, Magdalena B. Rother, Melanie van der Woude, Roman Gonzalez-Prieto, Adi Yifrach, Avital Parnas, Rashmi G. Shah, Tia Tyrsett Kuo, Daphne E. C. Boer, Jin Cai, Angela Kragten, Hyun-Suk Kim, Orlando D. Scharer, Alfred C. O. Vertegaal, Girish M. Shah, Sheera Adar, Hannes Lans, Haico van Attikum, Andreas G. Ladurner, Martijn S. Luijsterburg
Summary: Cells employ global genome nucleotide excision repair to repair a broad spectrum of genomic DNA lesions. Here, the authors reveal how chromatin is primed for repair, providing insight into mechanisms of chromatin plasticity during DNA repair.
NATURE COMMUNICATIONS
(2022)
Article
Environmental Sciences
Ganjai Vikram Paul, Ya-Yun Huang, Yu-Ning Wu, Tsung-Nan Ho, Hsin-I. Hsiao, Todd Hsu
Summary: This study investigated the effects of aluminum on DNA damage repair using zebrafish embryos as a model system. The results showed that aluminum enhances its genotoxicity by inhibiting the nucleotide excision repair (NER) capacity.
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
(2022)
Article
Biochemistry & Molecular Biology
Sunbok Jang, Matthew A. Schaich, Cindy Khuu, Brittani L. Schnable, Chandrima Majumdar, Simon C. Watkins, Sheila S. David, Bennett Van Houten
Summary: The study reveals that UV-DDB can stimulate MUTYH turnover rate, increase complex formation between MUTYH and UV-DDB, and enhance MUTYH mobility and dissociation rate during 8-oxoG:A repair, suggesting a facilitative role of UV-DDB in MUTYH activity at abasic sites.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Jennifer Le, Jung-Hyun Min
Summary: Xeroderma pigmentosum C (XPC) is an important factor in the genome nucleotide excision repair pathway. Mutations in the XPC gene can lead to XP cancer predisposition syndrome, increasing susceptibility to sunlight-induced cancers. The lack of a high-resolution 3D structure for human XPC makes it challenging to assess the impact of mutations/variations on its structure.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Multidisciplinary Sciences
Jeremy Sandoz, Max Cigrang, Amelie Zachayus, Philippe Catez, Lise-Marie Donnio, Clemence Elly, Jadwiga Nieminuszczy, Pietro Berico, Cathy Braun, Sergey Alekseev, Jean-Marc Egly, Wojciech Niedzwiedz, Giuseppina Giglia-Mari, Emmanuel Compe, Frederic Coin
Summary: The exonuclease EXD2 plays a role in the recovery of class II gene transcription after UV irradiation. It moves from mitochondria to the nucleus where it interacts with RNA Pol II and degrades newly synthesized mRNA, allowing transcription to resume after DNA repair. Lack of EXD2 impairs mRNA synthesis recovery and reduces cell survival after UV irradiation, but does not affect DNA repair. Overexpression of wild-type EXD2 restores mRNA synthesis recovery and cell survival. EXD2 is relocated from mitochondria to the nucleus upon UV irradiation, where it interacts transiently with chromatin-bound RNA Pol II to promote the degradation of nascent mRNAs. In vitro experiments show that EXD2 primarily interacts with elongation-blocked RNA Pol II and efficiently degrades mRNA. Overall, this study highlights the crucial role of EXD2 in the transcriptional response to genotoxic attack, where it interacts with elongation-stalled RNA Pol II on chromatin to potentially degrade the associated nascent mRNA, allowing transcription restart after DNA repair.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Hiral Mistry, Gagan Deep Gupta
Summary: Transcription-coupled repair (TCR) is a pathway for the repair of DNA lesions that block transcription. UV-stimulated scaffold protein A (UVSSA) is a cofactor involved in the stabilization of the TCR complex and recruitment of DNA-repair machinery. Human UVSSA interacts with DNA and RNA and has at least two nucleic acid binding regions, the N-terminal domain and C-terminal tail region. This study provides insights into the functional characteristics of UVSSA proteins.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2023)
Article
Genetics & Heredity
Sergey Nikolaev, Andrey A. Yurchenko, Alain Sarasin
Summary: XP patients have a significantly increased risk of developing internal tumors compared to the general population, with the risk being 34 times higher and tumors occurring 50 years earlier. XP-C patients have the highest risk, particularly among those aged 0-20 years. The most common types of internal tumors observed in XP patients include central nervous system tumors, hematological malignancies, thyroid tumors, and gynecological tumors. The type of mutation in the XPC gene is associated with different classes of internal tumors. The findings highlight the importance of early prevention and detection of internal tumors in XP patients.
ORPHANET JOURNAL OF RARE DISEASES
(2022)
Article
Biochemistry & Molecular Biology
Anatoly A. Bulygin, Victoria N. Syryamina, Aleksandra A. Kuznetsova, Darya S. Novopashina, Sergei A. Dzuba, Nikita A. Kuznetsov
Summary: This study investigated the molecular events in the process of damage recognition by Apurinic/apyrimidinic endonuclease 1 (APE1) through DEER spectroscopy and kinetic analysis. The results showed that specific mutants of APE1 had higher activity in recognizing and repairing damaged DNA, revealing the factors that affect its substrate specificity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Mariangela Sabatella, Alex Pines, Jana Slyskova, Wim Vermeulen, Hannes Lans
CELLULAR AND MOLECULAR LIFE SCIENCES
(2020)
Article
Biochemistry & Molecular Biology
Frauke Liebelt, Joost Schimmel, Matty Verlaan-de Vries, Esra Klemann, Martin E. van Royen, Yana van der Weegen, Martijn S. Luijsterburg, Leon H. Mullenders, Alex Pines, Wim Vermeulen, Alfred C. O. Vertegaal
NUCLEIC ACIDS RESEARCH
(2020)
Article
Multidisciplinary Sciences
Elisabeth Anne Adanma Obara, Diana Aguilar-Morante, Rikke Darling Rasmussen, Alex Frias, Kristoffer Vitting-Serup, Yi Chieh Lim, Kirstine Juul Elbaek, Henriette Pedersen, Lina Vardouli, Kamilla Ellermann Jensen, Jane Skjoth-Rasmussen, Jannick Brennum, Lucie Tuckova, Robert Strauss, Christoffel Dinant, Jiri Bartek, Petra Hamerlik
NATURE COMMUNICATIONS
(2020)
Article
Multidisciplinary Sciences
Cristina Ribeiro-Silva, Mariangela Sabatella, Angela Helfricht, Jurgen A. Marteijn, Arjan F. Theil, Wim Vermeulen, Hannes Lans
NATURE COMMUNICATIONS
(2020)
Article
Cell Biology
Mariangela Sabatella, Karen L. Thijssen, Carlota Davo-Martinez, Wim Vermeulen, Hannes Lans
Summary: Research has shown that there are tissue-specific differences in DNA repair activity, with muscle cells appearing to be more resistant to the effects of DNA damage compared to neurons.
Article
Oncology
Malene Bredahl Hansen, Maria Postol, Siri Tvingsholm, Inger Odum Nielsen, Tiina Naumanen Dietrich, Pietri Puustinen, Kenji Maeda, Christoffel Dinant, Robert Strauss, David Egan, Marja Jaattela, Tuula Kallunki
Summary: This study identified several efficient inhibitors of invasive growth in HER2 positive cancers resistant to first and second-line treatments, by targeting lysosomal pathways downstream of ErbB2. The drugs classified into different groups based on their ability to induce autophagy and/or lysosomal membrane permeabilization, providing potential targets for preventing cancer cell spreading. Additionally, these drugs possess anti-inflammatory activities, suggesting they could be used as multipurpose drugs targeting both infection/inflammation and cancer spreading simultaneously.
Article
Cell Biology
Ying Zhang, Imke K. Mandemaker, Syota Matsumoto, Oded Foreman, Christopher P. Holland, Whitney R. Lloyd, Kaoru Sugasawa, Wim Vermeulen, Jurgen A. Marteijn, Paul J. Galardy
Summary: Nucleotide excision repair pathway is essential for fixing DNA damage, and the UV-DDB complex plays a key role in recognizing and repairing UV-induced lesions. The tumor suppressor USP44 deubiquitinates DDB2 to prevent premature degradation, ensuring proper recruitment of repair components. Lack of USP44 leads to impaired repair and increases susceptibility to NER-induced tumors.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Cell Biology
Marit E. Geijer, Di Zhou, Kathiresan Selvam, Barbara Steurer, Chirantani Mukherjee, Bastiaan Evers, Simona Cugusi, Marvin van Toorn, Melanie van der Woude, Roel C. Janssens, Yannick P. Kok, Wenzhi Gong, Anja Raams, Calvin S. Y. Lo, Joyce H. G. Lebbink, Bart Geverts, Dalton A. Plummer, Karel Bezstarosti, Arjan F. Theil, Richard Mitter, Adriaan B. Houtsmuller, Wim Vermeulen, Jeroen A. A. Demmers, Shisheng Li, Marcel A. T. M. van Vugt, Hannes Lans, Rene Bernards, Jesper Q. Svejstrup, Arnab Ray Chaudhuri, John J. Wyrick, Jurgen A. Marteijn
Summary: Correct transcription is crucial for life, and cells have intricate mechanisms to counteract transcription-blocking lesions. The elongation factor ELOF1 plays an important role in the transcription stress response following DNA damage, protecting the transcription machinery via two distinct mechanisms.
NATURE CELL BIOLOGY
(2021)
Article
Biology
Karen L. Thijssen, Melanie van der Woude, Carlota Davo-Martinez, Dick H. W. Dekkers, Mariangela Sabatella, Jeroen A. A. Demmers, Wim Vermeulen, Hannes Lans
Summary: The TFIIH complex is essential for transcription and nucleotide excision repair, with mutations in its smallest subunit TTDA/GTF2H5 leading to trichothiodystrophy. While TTDA/GTF2H5 knockout mice are not viable, a C. elegans model shows GTF-2H5 deficiency is compatible with life and can be used for studying the disease's pathogenesis.
COMMUNICATIONS BIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Alba Muniesa-Vargas, Arjan F. Theil, Cristina Ribeiro-Silva, Wim Vermeulen, Hannes Lans
Summary: The XPG/ERCC5 endonuclease is the causative gene for Xeroderma Pigmentosum complementation group G. It plays a critical role in removing DNA damage in nucleotide excision repair and has additional important functions in genome maintenance, such as protecting replication forks and resolving R-loops. XPG deficiency is associated with various disease phenotypes.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Multidisciplinary Sciences
Daniel Gomez-Cabello, Giorgios Pappas, Diana Aguilar-Morante, Christoffel Dinant, Jiri Bartek
Summary: RNA plays a crucial role in DNA damage repair. This study demonstrates that the interplay of RNAPII-generated nascent RNA, RNA:DNA hybrids, and the resection factor CtIP guides the choice of DNA double-strand break repair pathway towards error-free homologous recombination.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
Ditte L. Fogde, Cristina P. R. Xavier, Kristina Balnyte, Lya K. K. Holland, Kamilla Stahl-Meyer, Christoffel Dinant, Elisabeth Corcelle-Termeau, Cristina Pereira-Wilson, Kenji Maeda, Marja Jaattela
Summary: Ursolic acid, a naturally occurring compound, has anti-inflammatory and anti-tumor effects. This study reveals that its anti-cancer activity is achieved by targeting lysosomal function, disrupting apoptosis and autophagy pathways to kill cancer cells. Combination treatment with cationic amphiphilic drugs can enhance the anti-cancer effect of ursolic acid.
Article
Biochemistry & Molecular Biology
Carlota Davo-Martinez, Angela Helfricht, Cristina Ribeiro-Silva, Anja Raams, Maria Tresini, Sidrit Uruci, Wiggert A. van Cappellen, Nitika Taneja, Jeroen A. A. Demmers, Alex Pines, Arjan F. Theil, Wim Vermeulen, Hannes Lans
Summary: The SWI/SNF family of ATP-dependent chromatin remodeling complexes is frequently mutated in cancer and is involved in multiple DNA damage response mechanisms. Different subunits of the BAF, PBAF and ncBAF complexes are recruited to double-strand breaks (DSBs) in a transcription-dependent manner and promote homologous recombination. PBAF and ncBAF complexes facilitate RNA polymerase II eviction and initiate transcriptional silencing near DNA damage, while BAF complex helps to maintain this silencing. ARID1A-containing BAF complexes aid in R-loop resolution and DNA repair by promoting the recruitment of RNaseH1 and RAD52.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Elena Botta, Arjan F. Theil, Anja Raams, Giuseppina Caligiuri, Sarah Giachetti, Silvia Bione, Maria Accadia, Anita Lombardi, Desiree E. C. Smith, Marisa Mendes, Sigrid M. A. Swagemakers, Peter J. Van der Spek, Gajja S. Salomons, Jan H. J. Hoeijmakers, Dhanya Yesodharan, Sheela Nampoothiri, Tomoo Ogi, Alan R. Lehmann, Donata Orioli, Wim Vermeulen
Summary: Trichothiodystrophy (TTD) is a rare hereditary neurodevelopmental disorder characterized by sulfur-deficient brittle hair, nails, and scaly skin, with highly variable clinical features. New gene defects have been identified to cause the non-photosensitive forms of TTD (NPS-TTD), impacting the stability of tRNA synthetases and protein translation. This study redefines TTD as a syndrome where proteins involved in gene expression are unstable, affecting both translation and transcription.
HUMAN MOLECULAR GENETICS
(2021)
Meeting Abstract
Dermatology
A. Theil, A. Pines, M. Sabatella, A. Raams, H. Lans, W. Vermeulen
BRITISH JOURNAL OF DERMATOLOGY
(2019)
