Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest
Open Access
- 13 September 2004
- journal article
- Published by Rockefeller University Press in The Journal of cell biology
- Vol. 166 (6), 801-813
- https://doi.org/10.1083/jcb.200405128
Abstract
Bloom's syndrome is a rare autosomal recessive genetic disorder characterized by chromosomal aberrations, genetic instability, and cancer predisposition, all of which may be the result of abnormal signal transduction during DNA damage recognition. Here, we show that BLM is an intermediate responder to stalled DNA replication forks. BLM colocalized and physically interacted with the DNA damage response proteins 53BP1 and H2AX. Although BLM facilitated physical interaction between p53 and 53BP1, 53BP1 was required for efficient accumulation of both BLM and p53 at the sites of stalled replication. The accumulation of BLM/53BP1 foci and the physical interaction between them was independent of γ-H2AX. The active Chk1 kinase was essential for both the accurate focal colocalization of 53BP1 with BLM and the consequent stabilization of BLM. Once the ATR/Chk1- and 53BP1-mediated signal from replicational stress is received, BLM functions in multiple downstream repair processes, thereby fulfilling its role as a caretaker tumor suppressor.Keywords
This publication has 43 references indexed in Scilit:
- p53's double life: transactivation-independent repression of homologous recombinationTrends in Genetics, 2004
- Bloom syndrome cells undergo p53-dependent apoptosis and delayed assembly of BRCA1 and NBS1 repair complexes at stalled replication forksThe Journal of cell biology, 2003
- p53 Binding Protein 53BP1 Is Required for DNA Damage Responses and Tumor Suppression in MiceMolecular and Cellular Biology, 2003
- 53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancerNature, 2002
- Functional Link between BLM Defective in Bloom's Syndrome and the Ataxia-telangiectasia-mutated Protein, ATMPublished by Elsevier BV ,2002
- Bloom's syndrome protein is required for correct relocalization of RAD50/MRE11/NBS1 complex after replication fork arrestThe Journal of cell biology, 2002
- Potential Role for the BLM Helicase in Recombinational Repair via a Conserved Interaction with RAD51Published by Elsevier BV ,2001
- Diverged nuclear localization of Werner helicase in human and mouse cellsOncogene, 2001
- Phosphorylation and Rapid Relocalization of 53BP1 to Nuclear Foci upon DNA DamageMolecular and Cellular Biology, 2001
- DNA Helicases, Genomic Instability, and Human Genetic DiseaseAnnual Review of Genomics and Human Genetics, 2000