CHD7 and 53BP1 regulate distinct pathways for the re-ligation of DNA double-strand breaks

Chromatin structure is dynamically reorganized at multiple levels in response to DNA double-strand breaks (DSBs). Yet, how the different steps of chromatin reorganization are coordinated in space and time to differentially regulate DNA repair pathways is insufficiently understood. Here, we identify...

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Published in:Nature communications Vol. 11; no. 1; pp. 5775 - 19
Main Authors: Rother, Magdalena B., Pellegrino, Stefania, Smith, Rebecca, Gatti, Marco, Meisenberg, Cornelia, Wiegant, Wouter W., Luijsterburg, Martijn S., Imhof, Ralph, Downs, Jessica A., Vertegaal, Alfred C. O., Huet, Sébastien, Altmeyer, Matthias, van Attikum, Haico
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 13.11.2020
Nature Publishing Group
Nature Portfolio
Subjects:
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Acetylation
Cell Line, Tumor
CHARGE syndrome
Chromatin - metabolism
Chromatin remodeling
Damage
Deoxyribonucleic acid
DNA
DNA Breaks, Double-Stranded
DNA damage
DNA End-Joining Repair
DNA helicase
DNA Helicases - metabolism
DNA Ligase ATP - metabolism
DNA repair
DNA structure
DNA-Binding Proteins - metabolism
Double-strand break repair
Green Fluorescent Proteins - metabolism
Histone Deacetylase 1 - metabolism
Homology
Humanities and Social Sciences
Humans
Ku Autoantigen - metabolism
Life Sciences
LIG4 protein
multidisciplinary
Non-homologous end joining
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) polymerase
Proteins
Repair
Science
Science (multidisciplinary)
Tumor Suppressor p53-Binding Protein 1 - metabolism
Ubiquitin-Protein Ligases - metabolism
Yeast
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary:Chromatin structure is dynamically reorganized at multiple levels in response to DNA double-strand breaks (DSBs). Yet, how the different steps of chromatin reorganization are coordinated in space and time to differentially regulate DNA repair pathways is insufficiently understood. Here, we identify the Chromodomain Helicase DNA Binding Protein 7 (CHD7), which is frequently mutated in CHARGE syndrome, as an integral component of the non-homologous end-joining (NHEJ) DSB repair pathway. Upon recruitment via PARP1-triggered chromatin remodeling, CHD7 stimulates further chromatin relaxation around DNA break sites and brings in HDAC1/2 for localized chromatin de-acetylation. This counteracts the CHD7-induced chromatin expansion, thereby ensuring temporally and spatially controlled ‘chromatin breathing’ upon DNA damage, which we demonstrate fosters efficient and accurate DSB repair by controlling Ku and LIG4/XRCC4 activities. Loss of CHD7-HDAC1/2-dependent cNHEJ reinforces 53BP1 assembly at the damaged chromatin and shifts DSB repair to mutagenic NHEJ, revealing a backup function of 53BP1 when cNHEJ fails. Chromatin is dynamically remodeled in response to DNA damage in favour of repair. Here the authors reveal how the chromatin remodeler CHD7 and chromatin binding protein 53BP1 regulate distinct DNA repair pathways.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-020-19502-5