ATM-Chk2-p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency

BRCA1 is a checkpoint and DNA damage repair gene that secures genome integrity. We have previously shown that mice lacking full-length Brca1 (Brca1(Delta 11/Delta 11)) die during embryonic development. Haploid loss of p53 completely rescues embryonic lethality, and adult Brca1(Delta 11/Delta 11)p53(+/-) mice display cancer susceptibility and premature aging. Here, we show that reduced expression and/or the absence of Chk2 allow Brca1(Delta 11/Delta 11) mice to escape from embryonic lethality. Compared to Brca1(Delta 11/Delta 11)p53(+/-) mice, lifespan of Brca1(Delta 11/Delta 11)Chk2(-/-) mice was remarkably extended. Analysis of Brca1(Delta 11/Delta 11)Chk2(-/-) mice revealed that p53-dependent apoptosis and growth defect caused by Brca1 deficiency are significantly attenuated in rapidly proliferating organs. However, in later life, Brca1(Delta 11/Delta 11)Chk2(-/-) female mice developed multiple tumors. Furthermore, haploid loss of ATM also rescued Brca1 deficiency-associated embryonic lethality and premature aging. Thus, in response to Brca1 deficiency, the activation of the ATM-Chk2-p53 signaling pathway contributes to the suppression of neoplastic transformation, while leading to compromised organismal homeostasis. Our data highlight how accurate maintenance of genomic integrity is critical for the suppression of both aging and malignancy, and provide a further link between aging and cancer.