Broering Tyler J, Alavattam Kris G, Sadreyev Ruslan I, Ichijima Yosuke, Kato Yasuko, Hasegawa Kazuteru, Camerini-Otero R Daniel, Lee Jeannie T, Andreassen Paul R, Namekawa Satoshi H
Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229Division of Reproductive Sciences and Division of Developmental Biology, Perinatal Institute, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229.
Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Department of Pathology, and Department of Genetics, Harvard Medical School, Boston, MA 02114 Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Department of Pathology, and Department of Genetics, Harvard Medical School, Boston, MA 02114 Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Department of Pathology, and Department of Genetics, Harvard Medical School, Boston, MA 02114 Howard Hughes Medical Institute, Department of Molecular Biology, Massachusetts General Hospital, Department of Pathology, and Department of Genetics, Harvard Medical School, Boston, MA 02114.
J Cell Biol. 2014 Jun 9;205(5):663-75. doi: 10.1083/jcb.201311050.
During meiosis, DNA damage response (DDR) proteins induce transcriptional silencing of unsynapsed chromatin, including the constitutively unsynapsed XY chromosomes in males. DDR proteins are also implicated in double strand break repair during meiotic recombination. Here, we address the function of the breast cancer susceptibility gene Brca1 in meiotic silencing and recombination in mice. Unlike in somatic cells, in which homologous recombination defects of Brca1 mutants are rescued by 53bp1 deletion, the absence of 53BP1 did not rescue the meiotic failure seen in Brca1 mutant males. Further, BRCA1 promotes amplification and spreading of DDR components, including ATR and TOPBP1, along XY chromosome axes and promotes establishment of pericentric heterochromatin on the X chromosome. We propose that BRCA1-dependent establishment of X-pericentric heterochromatin is critical for XY body morphogenesis and subsequent meiotic progression. In contrast, BRCA1 plays a relatively minor role in meiotic recombination, and female Brca1 mutants are fertile. We infer that the major meiotic role of BRCA1 is to promote the dramatic chromatin changes required for formation and function of the XY body.
在减数分裂过程中，DNA损伤反应（DDR）蛋白会诱导未联会染色质的转录沉默，包括雄性中组成型未联会的XY染色体。DDR蛋白也参与减数分裂重组过程中的双链断裂修复。在此，我们探讨乳腺癌易感基因Brca1在小鼠减数分裂沉默和重组中的功能。与体细胞不同，在体细胞中Brca1突变体的同源重组缺陷可通过缺失53bp1得到挽救，而缺失53BP1并不能挽救Brca1突变雄性小鼠中出现的减数分裂失败。此外，BRCA1促进DDR组分（包括ATR和TOPBP1）沿XY染色体轴的扩增和扩散，并促进X染色体上着丝粒周围异染色质的形成。我们提出，依赖BRCA1的X着丝粒周围异染色质的形成对于XY体形态发生及随后的减数分裂进程至关重要。相比之下，BRCA1在减数分裂重组中起相对较小的作用，雌性Brca1突变体可育。我们推断，BRCA1在减数分裂中的主要作用是促进XY体形成和功能所需的显著染色质变化。
