FANCD2 influences replication fork processes and genome stability in response to clustered DSBs

Jiayun Zhu, Fengtao Su, Shibani Mukherjee, Eiichiro Mori, Burong Hu, Aroumougame Asaithamby

Research output: Contribution to journalArticle

11 Citations (Scopus)

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

Original languageEnglish (US)
Pages (from-to)1809-1822
Number of pages14
JournalCell Cycle
Volume14
Issue number12
DOIs
StatePublished - Jan 1 2015

Fingerprint

Linear Energy Transfer
Genomic Instability
Radiation
Fanconi Anemia
Maintenance
Neoplasms
Chromosome Segregation
Double-Stranded DNA Breaks
DNA Replication
S Phase
Chromosome Aberrations
DNA Repair
DNA Damage
Growth

Keywords

  • Clustered DSBs
  • DNA replication
  • FANCD2
  • Genome instability
  • High-LET radiation

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

Cite this

FANCD2 influences replication fork processes and genome stability in response to clustered DSBs. / Zhu, Jiayun; Su, Fengtao; Mukherjee, Shibani; Mori, Eiichiro; Hu, Burong; Asaithamby, Aroumougame.

In: Cell Cycle, Vol. 14, No. 12, 01.01.2015, p. 1809-1822.

Research output: Contribution to journalArticle

Zhu, Jiayun ; Su, Fengtao ; Mukherjee, Shibani ; Mori, Eiichiro ; Hu, Burong ; Asaithamby, Aroumougame. / FANCD2 influences replication fork processes and genome stability in response to clustered DSBs. In: Cell Cycle. 2015 ; Vol. 14, No. 12. pp. 1809-1822.
@article{c4d316f35cc94558984cc410238a6a4c,
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",
keywords = "Clustered DSBs, DNA replication, FANCD2, Genome instability, High-LET radiation",
author = "Jiayun Zhu and Fengtao Su and Shibani Mukherjee and Eiichiro Mori and Burong Hu and Aroumougame Asaithamby",
year = "2015",
month = "1",
day = "1",
doi = "10.1080/15384101.2015.1036210",
language = "English (US)",
volume = "14",
pages = "1809--1822",
journal = "Cell Cycle",
issn = "1538-4101",
publisher = "Landes Bioscience",
number = "12",

}

TY - JOUR

T1 - FANCD2 influences replication fork processes and genome stability in response to clustered DSBs

AU - Zhu, Jiayun

AU - Su, Fengtao

AU - Mukherjee, Shibani

AU - Mori, Eiichiro

AU - Hu, Burong

AU - Asaithamby, Aroumougame

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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

AB - 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

KW - Clustered DSBs

KW - DNA replication

KW - FANCD2

KW - Genome instability

KW - High-LET radiation

UR - http://www.scopus.com/inward/record.url?scp=84943811830&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84943811830&partnerID=8YFLogxK

U2 - 10.1080/15384101.2015.1036210

DO - 10.1080/15384101.2015.1036210

M3 - Article

C2 - 26083937

AN - SCOPUS:84943811830

VL - 14

SP - 1809

EP - 1822

JO - Cell Cycle

JF - Cell Cycle

SN - 1538-4101

IS - 12

ER -