Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest.
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 gamma-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.
Sengupta
Sagar
S
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Robles
Ana I
AI
Linke
Steven P
SP
Sinogeeva
Natasha I
NI
Zhang
Ran
R
Pedeux
Remy
R
Ward
Irene M
IM
Celeste
Arkady
A
Nussenzweig
André
A
Chen
Junjie
J
Halazonetis
Thanos D
TD
Harris
Curtis C
CC
D001816:Bloom Syndrome / Q000201:enzymology*; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000378:metabolism; D002352:Carrier Proteins; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D018613:Microscopy, Confocal; D010750:Phosphoproteins; D010766:Phosphorylation; D011233:Precipitin Tests; D011494:Protein Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering; D016196:S Phase; D000071857:Tumor Suppressor p53-Binding Protein 1
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D034741:RNA, Small Interfering; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D004265:DNA Helicases; D001973:Bromodeoxyuridine; D006918:Hydroxyurea