Chk1-Mediated Phosphorylation of FANCE Is Required for the Fanconi Anemia/BRCA Pathway

Wang, XiaoZhe; Kennedy, Richard D.; Ray, Kallol; Stuckert, Patricia; Ellenberger, Tom; D’Andrea, Alan D.

doi:10.1128/mcb.02357-06

Cited by 127 publications

(110 citation statements)

References 30 publications

Supporting

Mentioning

106

Contrasting

Order By: Relevance

“…In addition, two recent studies indicate that Chk1 and/or Rad1 are involved in regulating FA pathway activation in response to DNA damage (45,47), raising the possibility that FANCM might have functions downstream of Chk1 in the ATRdependent checkpoint signaling. In summary, we propose that FANCM has multiple roles during chromosomal replication.…”

Section: Discussionmentioning

confidence: 99%

The Fanconi Anemia Protein FANCM Is Controlled by FANCD2 and the ATR/ATM Pathways

Sobeck¹,

Stone

Landais

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

In addition to monoubiquitination by the FA core complex, FANCD2 and FANCI are phosphorylated by the two major cell cycle checkpoint kinases, ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related),y in response to DNA damage (2-6). ATM-dependent phosphorylation of FANCD2 occurs following ionizing irradiation and is required for activation of the ionizing irradiation-induced intra-S phase checkpoint (4). ATR-dependent phosphorylation of FANCD2 is triggered by various types of DNA damage, including replication stress, and is required for the interstrand cross-link-induced intra-S phase checkpoint response (2, 3). Moreover, phosphorylation by ATR is required for efficient FANCD2 monoubiquitination in response to DNA damage, suggesting that the FA pathway might participate in ATR-dependent coordination of the S phase of the cell cycle (3, 7).The recent identification of a highly conserved FA core complex member, FANCM (8, 9), indicates a direct role of FA pathway proteins in repair steps at sites of DNA damage. FANCM is a homolog of the archaebacterial Hef protein (helicase-associated endonuclease for fork-structured DNA) and contains two DNA processing domains: a DEAH box helicase domain and an XPF/ERCC4-like endonuclease domain. FANCM has ATP-dependent DNA translocase activity and can dissociate DNA triple helices in vitro (8). Moreover, FANCM binds Holliday junctions and DNA replication fork structures in vitro and promotes ATP-dependent branch point migration, suggesting that FANCM might be involved in DNA processing at stalled replication forks (10,11). In human cells, FANCM localizes to chromatin and is required for chromatin recruitment of other FA core complex proteins (8,12). FANCM is phosphorylated during both the M and S phases and in response to DNA-damaging agents (8,12,13). Interestingly, DNA damage-induced phosphorylation of FANCM is independent of the FA core complex (8), suggesting that FANCM is controlled by other, as yet unknown upstream components of the DNA damage response. Here, we used cell-free Xenopus egg extracts to investigate the role of FANCM during replication and in the DNA damage response. We show that Xenopus FANCM (xFANCM) binds chromatin in a replication-dependent manner and is phosphorylated during unperturbed replication as well as in response to various DNA damage structures. Both chromatin recruitment and phosphorylation of xFANCM are partially controlled by xFANCD2, suggesting feedback signaling from xFANCD2 to the upstream xFA core complex via regulation of xFANCM. In addition, chromatin recruitment during unperturbed replication and activation of xFANCM in response to DNA damage are controlled by the xATR and xATM cell cycle kinases.

show abstract

Section: Discussionmentioning

confidence: 99%

The Fanconi Anemia Protein FANCM Is Controlled by FANCD2 and the ATR/ATM Pathways

Sobeck¹,

Stone

Landais

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…This is in part due to the fact that CHK1 supports several repair pathways required for productive proliferation of normal cells, including homologous recombination 31 and Fanconi anemia pathways. 46 We propose that NEK11 could be a more rational drug target than CHK1, since NEK11 most likely does not control these repair pathways required for cell proliferation in general. Furthermore, our tissue microarray data suggest that NEK11 expression is increased in some adenomas and carcinomas, and it therefore appears plausible that NEK11 inhibition may sensitize these tumors to chemotherapy or IR.…”

Section: Nek11 As a Potential Drug Targetmentioning

confidence: 95%

NEK11−Linking CHK1 and CDC25A in DNA damage checkpoint signaling

Sørensen

Melixetian

Klein³

et al. 2010

Cell Cycle

View full text Add to dashboard Cite

“…Once activated by ATR, Chk1 promotes cell-cycle arrest via phosphorylation of Cdc25 phosphatases resulting in their destruction or sequestration, preventing the reversal of inhibitory phosphorylation of the cyclin-dependent kinases (5). Chk1 also inhibits firing of replication origins (6), stabilizes stalled replication forks (7), and regulates proteins involved with DNA repair (8,9). A structurally dissimilar checkpoint kinase, Chk2 is activated by ataxia telangiectasia mutated (ATM) in response to double strand breaks; it promotes both Cdc25 inactivation and p53-dependent cell-cycle arrest.…”

Section: Introductionmentioning

confidence: 99%

The Checkpoint Kinase Inhibitor AZD7762 Potentiates Chemotherapy-Induced Apoptosis of p53-Mutated Multiple Myeloma Cells

Landau

McNeely

Nair

et al. 2012

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

DNA cross-linking agents are frequently used in the treatment of multiple myeloma-generating lesions, which activate checkpoint kinase 1 (Chk1), a critical transducer of the DNA damage response. Chk1 activation promotes cell survival by regulating cell-cycle arrest and DNA repair following genotoxic stress. The ability of AZD7762, an ATP-competitive Chk1/2 inhibitor to increase the efficacy of the DNA-damaging agents bendamustine, melphalan, and doxorubicin was examined using four human myeloma cell lines, KMS-12-BM, KMS-12-PE, RPMI-8226, and U266B1. The in vitro activity of AZD7762 as monotherapy and combined with alkylating agents and the "novel" drug bortezomib was evaluated by studying its effects on cytotoxicity, signaling, and apoptotic pathways. The Chk1/2 inhibitor AZD7762 potentiated the antiproliferative effects of bendamustine, melphalan, and doxorubicin but not bortezomib in multiple myeloma cell lines that were p53-deficient. Increased gH2AX staining in cells treated with bendamustine or melphalan plus AZD7762 indicates a greater degree of DNA damage with combined therapy. Abrogation of the G 2 -M checkpoint by AZD7762 resulted in mitotic catastrophe with ensuing apoptosis evidenced by PARP and caspase-3 cleavage. In summary, the cytotoxic effects of bendamustine, melphalan and doxorubicin on p53-deficient multiple myeloma cell lines were enhanced by the coadministration of AZD7762. These data provide a rationale for testing these combinations in patients with relapsed and/or refractory multiple myeloma.

show abstract

Chk1-Mediated Phosphorylation of FANCE Is Required for the Fanconi Anemia/BRCA Pathway

Cited by 127 publications

References 30 publications

The Fanconi Anemia Protein FANCM Is Controlled by FANCD2 and the ATR/ATM Pathways

The Fanconi Anemia Protein FANCM Is Controlled by FANCD2 and the ATR/ATM Pathways

NEK11−Linking CHK1 and CDC25A in DNA damage checkpoint signaling

The Checkpoint Kinase Inhibitor AZD7762 Potentiates Chemotherapy-Induced Apoptosis of p53-Mutated Multiple Myeloma Cells

Contact Info

Product

Resources

About