Journal
NUCLEIC ACIDS RESEARCH
Volume 42, Issue 13, Pages 8473-U191Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gku565
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Funding
- Association for International Cancer Research [08-0084]
- Netherlands Organization for Scientific Research [863.08.022, 854.11.002, 912.12.132, 917.96.120]
- Horizon Zenith [93511042]
- European Research Council [340988-ERC_ID]
- FP7 Marie Curie International Training Network [316390]
- Erasmus MC Fellowship
- Human Frontiers Science Program [CDA]
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Chromatin compaction of deoxyribonucleic acid (DNA) presents a major challenge to the detection and removal of DNA damage. Helix-distorting DNA lesions that block transcription are specifically repaired by transcription-coupled nucleotide excision repair, which is initiated by binding of the CSB protein to lesion-stalled RNA polymerase II. Using live cell imaging, we identify a novel function for two distinct mammalian ISWI adenosine triphosphate (ATP)-dependent chromatin remodeling complexes in resolving lesion-stalled transcription. Human ISWI isoform SMARCA5/SNF2H and its binding partners ACF1 and WSTF are rapidly recruited to UV-C induced DNA damage to specifically facilitate CSB binding and to promote transcription recovery. SMARCA5 targeting to UV-C damage depends on transcription and histone modifications and requires functional SWI2/SNF2-ATPase and SLIDE domains. After initial recruitment to UV damage, SMARCA5 re-localizes away from the center of DNA damage, requiring its HAND domain. Our studies support a model in which SMARCA5 targeting to DNA damage-stalled transcription sites is controlled by an ATP-hydrolysis-dependent scanning and proofreading mechanism, highlighting how SWI2/SNF2 chromatin remodelers identify and bind nucleosomes containing damaged DNA.
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