TY - JOUR
T1 - Distinct versus overlapping functions of MDC1 and 53BP1 in DNA damage response and tumorigenesis
AU - Minter-Dykhouse, Katherine
AU - Ward, Irene
AU - Huen, Michael S.Y.
AU - Chen, Junjie
AU - Lou, Zhenkun
PY - 2008/6/2
Y1 - 2008/6/2
N2 - The importance of the DNA damage response (DDR) pathway in development, genomic stability, and tumor suppression is well recognized. Although 53BP1 and MDC1 have been recently identified as critical upstream mediators in the cellular response to DNA double-strand breaks, their relative hierarchy in the ataxia telangiectasia mutated (ATM) signaling cascade remains controversial. To investigate the divergent and potentially overlapping functions of MDC1 and 53BP1 in the ATM response pathway, we generated mice deficient for both genes. Unexpectedly, the loss of both MDC1 and 53BP1 neither significantly increases the severity of defects in DDR nor increases tumor incidence compared with the loss of MDC1 alone. We additionally show that MDC1 regulates 53BP1 foci formation and phosphorylation in response to DNA damage. These results suggest that MDC1 functions as an upstream regulator of 53BP1 in the DDR pathway and in tumor suppression.
AB - The importance of the DNA damage response (DDR) pathway in development, genomic stability, and tumor suppression is well recognized. Although 53BP1 and MDC1 have been recently identified as critical upstream mediators in the cellular response to DNA double-strand breaks, their relative hierarchy in the ataxia telangiectasia mutated (ATM) signaling cascade remains controversial. To investigate the divergent and potentially overlapping functions of MDC1 and 53BP1 in the ATM response pathway, we generated mice deficient for both genes. Unexpectedly, the loss of both MDC1 and 53BP1 neither significantly increases the severity of defects in DDR nor increases tumor incidence compared with the loss of MDC1 alone. We additionally show that MDC1 regulates 53BP1 foci formation and phosphorylation in response to DNA damage. These results suggest that MDC1 functions as an upstream regulator of 53BP1 in the DDR pathway and in tumor suppression.
UR - http://www.scopus.com/inward/record.url?scp=44649164582&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=44649164582&partnerID=8YFLogxK
U2 - 10.1083/jcb.200801083
DO - 10.1083/jcb.200801083
M3 - Article
C2 - 18504301
AN - SCOPUS:44649164582
SN - 0021-9525
VL - 181
SP - 727
EP - 735
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 5
ER -