CHD7 and 53BP1 regulate distinct pathways for the re-ligation of DNA double-strand breaks.
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Date
2020-11-13ICR Author
Author
Rother, MB
Pellegrino, S
Smith, R
Gatti, M
Meisenberg, C
Wiegant, WW
Luijsterburg, MS
Imhof, R
Downs, JA
Vertegaal, ACO
Huet, S
Altmeyer, M
van Attikum, H
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
Chromatin
Humans
DNA Helicases
Ubiquitin-Protein Ligases
DNA-Binding Proteins
Green Fluorescent Proteins
DNA Breaks, Double-Stranded
Histone Deacetylase 1
DNA End-Joining Repair
Ku Autoantigen
DNA Ligase ATP
Poly (ADP-Ribose) Polymerase-1
Tumor Suppressor p53-Binding Protein 1
Research team
Epigenetics and Genome Stability
Epigenetics and Genome Stability
Language
eng
Date accepted
2020-10-15
License start date
2020-11-13
Citation
Nature communications, 2020, 11 (1), pp. 5775 - ?
Publisher
NATURE RESEARCH