Widespread chromatin context-dependencies of DNA double-strand break repair proteins

DNA double-strand breaks are repaired by multiple pathways, including non-homologous end-joining (NHEJ) and microhomology-mediated end-joining (MMEJ). The balance of these pathways is dependent on the local chromatin context, but the underlying mechanisms are poorly understood. By combining knockout...

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Published in:Nature communications Vol. 15; no. 1; pp. 5334 - 14
Main Authors: Vergara, Xabier, Manjón, Anna G., de Haas, Marcel, Morris, Ben, Schep, Ruben, Leemans, Christ, Friskes, Anoek, Beijersbergen, Roderick L., Sanders, Mathijs A., Medema, René H., van Steensel, Bas
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 22.06.2024
Nature Publishing Group
Nature Portfolio
Subjects:
45/23
45/77
49
49/47
49/56
631/337/1427
631/553/2711
Ataxia Telangiectasia Mutated Proteins - genetics
Ataxia Telangiectasia Mutated Proteins - metabolism
BRCA2 protein
BRCA2 Protein - genetics
BRCA2 Protein - metabolism
Breast cancer
Chromatin
Chromatin - genetics
Chromatin - metabolism
Context
Deoxyribonucleic acid
DNA
DNA Breaks, Double-Stranded
DNA damage
DNA End-Joining Repair
DNA Repair
Double-strand break repair
Euchromatin
Euchromatin - genetics
Euchromatin - metabolism
Heterochromatin
Heterochromatin - genetics
Heterochromatin - metabolism
Humanities and Social Sciences
Humans
multidisciplinary
Non-homologous end joining
Proteins
Science
Science (multidisciplinary)
Synergism
Yeast
ISSN:2041-1723, 2041-1723
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Summary:DNA double-strand breaks are repaired by multiple pathways, including non-homologous end-joining (NHEJ) and microhomology-mediated end-joining (MMEJ). The balance of these pathways is dependent on the local chromatin context, but the underlying mechanisms are poorly understood. By combining knockout screening with a dual MMEJ:NHEJ reporter inserted in 19 different chromatin environments, we identified dozens of DNA repair proteins that modulate pathway balance dependent on the local chromatin state. Proteins that favor NHEJ mostly synergize with euchromatin, while proteins that favor MMEJ generally synergize with distinct types of heterochromatin. Examples of the former are BRCA2 and POLL, and of the latter the FANC complex and ATM. Moreover, in a diversity of human cancer types, loss of several of these proteins alters the distribution of pathway-specific mutations between heterochromatin and euchromatin. Together, these results uncover a complex network of proteins that regulate MMEJ:NHEJ balance in a chromatin context-dependent manner. DNA double-strand breaks are repaired by multiple pathways. The balance of these pathways depends on the local chromatin context, but the underlying mechanisms are poorly understood. Here the authors uncover a network of proteins that regulate pathway balance in a chromatin context-dependent manner.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-49232-x