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Functional cross talk between the Fanconi anemia and ATRX/DAXX histone chaperone pathways promotes replication fork recovery
- Source :
- Hum Mol Genet
- Publication Year :
- 2019
- Publisher :
- Oxford University Press (OUP), 2019.
-
Abstract
- Fanconi anemia (FA) is a chromosome instability syndrome characterized by increased cancer predisposition. Specifically, the FA pathway functions to protect genome stability during DNA replication. The central FA pathway protein, FANCD2, locates to stalled replication forks and recruits homologous recombination (HR) factors such as CtBP interacting protein (CtIP) to promote replication fork restart while suppressing new origin firing. Here, we identify alpha-thalassemia retardation syndrome X-linked (ATRX) as a novel physical and functional interaction partner of FANCD2. ATRX is a chromatin remodeler that forms a complex with Death domain-associated protein 6 (DAXX) to deposit the histone variant H3.3 into specific genomic regions. Intriguingly, ATRX was recently implicated in replication fork recovery; however, the underlying mechanism(s) remained incompletely understood. Our findings demonstrate that ATRX forms a constitutive protein complex with FANCD2 and protects FANCD2 from proteasomal degradation. ATRX and FANCD2 localize to stalled replication forks where they cooperate to recruit CtIP and promote MRE11 exonuclease-dependent fork restart while suppressing the firing of new replication origins. Remarkably, replication restart requires the concerted histone H3 chaperone activities of ATRX/DAXX and FANCD2, demonstrating that coordinated histone H3 variant deposition is a crucial event during the reinitiation of replicative DNA synthesis. Lastly, ATRX also cooperates with FANCD2 to promote the HR-dependent repair of directly induced DNA double-stranded breaks. We propose that ATRX is a novel functional partner of FANCD2 to promote histone deposition-dependent HR mechanisms in S-phase.
- Subjects :
- DNA Replication
X-linked Nuclear Protein
congenital, hereditary, and neonatal diseases and abnormalities
DNA Repair
Origin of replication
Cell Line
Histones
Gene Knockout Techniques
03 medical and health sciences
Histone H3
0302 clinical medicine
Death-associated protein 6
hemic and lymphatic diseases
Genetics
Humans
DNA Breaks, Double-Stranded
Molecular Biology
Genetics (clinical)
ATRX
030304 developmental biology
MRE11 Homologue Protein
0303 health sciences
biology
Fanconi Anemia Complementation Group D2 Protein
DNA replication
Recombinational DNA Repair
General Medicine
Chromatin Assembly and Disassembly
DNA Replication Fork
Chromatin
Cell biology
General Article One
Fanconi Anemia
Histone
030220 oncology & carcinogenesis
biology.protein
Rad51 Recombinase
Co-Repressor Proteins
Molecular Chaperones
Signal Transduction
Subjects
Details
- ISSN :
- 14602083 and 09646906
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....6265f1519931cf160f8ee6abb619fc4c