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Differences in 53BP1 and BRCA1 regulation between cycling and non-cycling cells

机译：循环和非循环细胞之间53BP1和BRCA1调控的差异

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BRCA1 and 53BP1 play decisive roles in the choice of DNA double-strand break repair mechanisms. BRCA1 promotes DNA end resection and homologous recombination (HR) during S/G2 phases of the cell cycle, while 53BP1 inhibits end resection and facilitates non-homologous end-joining (NHEJ), primarily during G1. This competitive relationship is critical for genome integrity during cell division. However, their relationship in the many cells in our body that are not cycling is unknown. We discovered profound differences in 53BP1 and BRCA1 regulation between cycling and non-cycling cells. Cellular growth arrest results in transcriptional downregulation of BRCA1 and activation of cathepsin-L (CTSL)-mediated degradation of 53BP1. Accordingly, growth-arrested cells do not form BRCA1 or 53BP1 ionizing radiation-induced foci (IRIF). Interestingly, cell cycle re-entry reverts this scenario, with upregulation of BRCA1, downregulation of CTSL, stabilization of 53BP1, and 53BP1 IRIF formation throughout the cycle, indicating that BRCA1 and 53BP1 are important in replicating cells and dispensable in non-cycling cells. We show that CTSL-mediated degradation of 53BP1, previously associated with aggressive breast cancers, is an endogenous mechanism of non-cycling cells to balance NHEJ (53BP1) and HR (BRCA1). Breast cancer cells exploit this mechanism to ensure genome stability and viability, providing an opportunity for targeted therapy.
机译：BRCA1和53BP1在DNA双链断裂修复机制的选择中起决定性作用。 BRCA1在细胞周期的S / G2期促进DNA末端切除和同源重组（HR），而53BP1抑制末端切除并促进非同源末端连接（NHEJ），主要是在G1期间。这种竞争关系对于细胞分裂过程中的基因组完整性至关重要。但是，它们在我们体内许多非循环细胞中的关系尚不清楚。我们发现循环细胞和非循环细胞在53BP1和BRCA1调控方面存在巨大差异。细胞生长停滞导致BRCA1的转录下调和组织蛋白酶L（CTSL）介导的53BP1降解的激活。因此，生长停滞的细胞不会形成BRCA1或53BP1电离辐射诱导灶（IRIF）。有趣的是，细胞周期的重新进入可以逆转这种情况，在整个周期中BRCA1的上调，CTSL的下调，53BP1的稳定和53BP1 IRIF的形成，表明BRCA1和53BP1在复制细胞中很重要，并且在非循环细胞中可分配。我们显示CTSL介导的53BP1降解，以前与侵袭性乳腺癌相关，是非循环细胞平衡NHEJ（53BP1）和HR（BRCA1）的内源性机制。乳腺癌细胞利用这种机制来确保基因组的稳定性和活力，从而为靶向治疗提供了机会。

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