期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 19, 期 7, 页码 671-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2320
关键词
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资金
- US National Institutes of Health [GM071440]
- Chinese Academy of Sciences
- State Key Development Program of Basic Research of China [2009CB918502]
- special grant for Stem Cell and Regenerative Medicine [XDA01040305]
- National Science Foundation [MCB-0547854]
- General Medicine and Cancer Institutes Collaborative Access Team, GM/CA-CAT
- Life Sciences Collaborative Access Team, LS-CAT
- The Northeastern Collaborative Access Team, NE-CAT) at the Advanced Photon Source at Argonne National Laboratory
- Shanghai Synchrotron Radiation Facility [BL17U1]
- US Department of Energy
ALKBH2 is a direct DNA repair dioxygenase guarding the mammalian genome against N-1-methyladenine, N-3-methylcytosine and 1,N-6-ethenoadenine damage. A prerequisite for repair is to identify these lesions in the genome. Here we present crystal structures of human ALKBH2 bound to different duplex DNAs. Together with computational and biochemical analyses, our results suggest that DNA interrogation by ALKBH2 has two previously unknown features: (i) ALKBH2 probes base-pair stability and detects base pairs with reduced stability, and (ii) ALKBH2 does not have nor need a damage-checking site, which is critical for preventing spurious base cleavage for several glycosylases. The demethylation mechanism of ALKBH2 insures that only cognate lesions are oxidized and reversed to normal bases, and that a flipped, non-substrate base remains intact in the active site. Overall, the combination of duplex interrogation and oxidation chemistry allows ALKBH2 to detect and process diverse lesions efficiently and correctly.
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