期刊
PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY
卷 163, 期 -, 页码 87-108出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pbiomolbio.2020.09.010
关键词
Sequence analysis; Motifs; Kinase; DNA repair; DNA damage Response; Crystal structure; Cryo-electron microscopy
资金
- NIH/NCI [P01 CA092584]
- NIH [R01 GM066099]
- Natural Sciences and Engineering Council (Canada) [RGPIN-2019-04829]
- Robert A. Welch Chemistry Chair
DNA-PKcs, a key member of the PIKK family, is widely distributed in invertebrates, fungi, plants, and protists, with highly conserved phosphorylation sites; it possesses unique amino acid sequence motifs and domains compared to other PIKKs; functional analysis of DNA-PKcs has important biological and medical implications.
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key member of the phosphatidylinositol-3 kinase-like (PIKK) family of protein kinases with critical roles in DNA-double strand break repair, transcription, metastasis, mitosis, RNA processing, and innate and adaptive immunity. The absence of DNA-PKcs from many model organisms has led to the assumption that DNA-PKcs is a vertebrate-specific PIKK. Here, we find that DNA-PKcs is widely distributed in invertebrates, fungi, plants, and protists, and that threonines 2609, 2638, and 2647 of the ABCDE cluster of phosphorylation sites are highly conserved amongst most Eukaryotes. Furthermore, we identify highly conserved amino acid sequence motifs and domains that are characteristic of DNA-PKcs relative to other PIKKs. These include residues in the Forehead domain and a novel motif we have termed YRPD, located in an alpha helix C-terminal to the ABCDE phosphorylation site loop. Combining sequence with biochemistry plus structural data on human DNA-PKcs unveils conserved sequence and conformational features with functional insights and implications. The defined generally progressive DNA-PKcs sequence diversification uncovers conserved functionality supported by Evolutionary Trace analysis, suggesting that for many organisms both functional sites and evolutionary pressures remain identical due to fundamental cell biology. The mining of cancer genomic data and germline mutations causing human inherited disease reveal that robust DNA-PKcs activity in tumors is detrimental to patient survival, whereas germline mutations compromising function are linked to severe immunodeficiency and neuronal degeneration. We anticipate that these collective results will enable ongoing DNA-PKcs functional analyses with biological and medical implications. (C) 2020 The Authors. Published by Elsevier Ltd.
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