MCPH1, also known as BRIT1, has recently been identified as a novel key regulatory gene of the DNA damage response pathway. MCPH1 is located on human chromosome 8p23.1, where human
cancers frequently show loss of heterozygosity. As such, MCPH1 is aberrantly expressed in many
malignancies, including breast and
ovarian cancers, and the function of MCPH1 has been implicated in
tumor suppression. However, it remains poorly understood whether MCPH1 deficiency leads to
tumorigenesis. Here we generated and studied both Mcph1(-/-) and Mcph1(-/-)p53(-/-) mice; we showed that Mcph1(-/-) mice developed
tumors with long latency, and that primary
lymphoma developed significantly earlier in Mcph1(-/-)p53(-/-) mice than in Mcph11(+/+)p53(-/-) and Mcph1(+/-)p53(-/-) mice. The Mcph1(-/-)p53(-/-)
lymphomas and derived murine embryonic fibroblasts (MEFs) were both more sensitive to irradiation. Mcph1 deficiency resulted in remarkably increased chromosome and chromatid breaks in Mcph1(-/-)p53(-/-)
lymphomas and MEFs, as determined by metaphase spread assay and spectral karyotyping analysis. In addition, Mcph1 deficiency significantly enhanced
aneuploidy as well as abnormal centrosome multiplication in Mcph1(-/-)p53(-/-) cells. Meanwhile, Mcph1 deficiency impaired double strand break (
DSB) repair in Mcph1(-/-)p53(-/-) MEFs as demonstrated by neutral Comet assay. Compared with Mcph1(+/+)p53(-/-) MEFs, homologous recombination and non-homologous end-joining activities were significantly decreased in Mcph1(-/-)p53(-/-) MEFs. Notably, reconstituted MCPH1 rescued the defects of
DSB repair and alleviated
chromosomal aberrations in Mcph1(-/-)p53(-/-) MEFs. Taken together, our data demonstrate MCPH1 deficiency promotes
genomic instability and increases
cancer susceptibility. Our study using knockout mouse models provides convincing genetic evidence that MCPH1 is a bona fide tumor suppressor gene. Its deficiency leading to defective DNA repair in
tumors can be used to develop novel targeted
cancer therapies in the future.