title: FANCD2 influences replication fork processes and genome stability in response to clustered DSBs.
abstract: Fanconi Anemia (FA) is a cancer predisposition syndrome and the factors defective in FA are involved in DNA replication, DNA damage repair and tumor suppression. Here, we show that FANCD2 is critical for genome stability maintenance in response to high-linear energy transfer (LET) radiation. We found that FANCD2 is monoubiquitinated and recruited to the sites of clustered DNA double-stranded breaks (DSBs) specifically in S/G2 cells after high-LET radiation. Further, FANCD2 facilitated the repair of clustered DSBs in S/G2 cells and proper progression of S-phase. Furthermore, lack of FANCD2 led to a reduced rate of replication fork progression and elevated levels of both replication fork stalling and new origin firing in response to high-LET radiation. Mechanistically, FANCD2 is required for correct recruitment of RPA2 and Rad51 to the sites of clustered DSBs and that is critical for proper processing of clustered DSBs. Significantly, FANCD2-decifient cells exhibited defective chromosome segregation, elevated levels of chromosomal aberrations, and anchorage-independent growth in response to high-LET radiation. These findings establish FANCD2 as a key factor in genome stability maintenance in response to high-LET radiation and as a promising target to improve cancer therapy.
authors.affiliation: a Department of Radiation Oncology ; Dallas , TX , USA.
authors.forename: Jiayun
authors.initials: J
authors.lastname: Zhu
authors.forename: Fengtao
authors.initials: F
authors.lastname: Su
authors.forename: Shibani
authors.initials: S
authors.lastname: Mukherjee
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Mori
authors.forename: Burong
authors.initials: B
authors.lastname: Hu
authors.forename: Aroumougame
authors.initials: A
authors.lastname: Asaithamby
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D005199:Fanconi Anemia / Q000235:genetics* / Q000532:radiotherapy; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics / Q000378:metabolism*; D016195:G2 Phase; D015894:Genome, Human; D042822:Genomic Instability; D006801:Humans; D018499:Linear Energy Transfer; D009369:Neoplasms / Q000235:genetics; D051135:Rad51 Recombinase / Q000235:genetics; D051716:Replication Protein A / Q000235:genetics; D016196:S Phase
chemical_list: C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D051716:Replication Protein A; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C516794:RPA2 protein, human
keywords: DNA replication; FANCD2; clustered DSBs; genome instability; high-LET radiation