53BP1：双链断裂的护送者。

53BP1: a DSB escort.

机构信息

Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, New York 10065, USA.

出版信息

Genes Dev. 2020 Jan 1;34(1-2):7-23. doi: 10.1101/gad.333237.119.

53BP1 is an enigmatic DNA damage response factor that gained prominence because it determines the efficacy of PARP1 inhibitory drugs (PARPi) in BRCA1-deficient cancers. Recent studies have elevated 53BP1 from its modest status of (yet another) DNA damage factor to master regulator of double-strand break (DSB) repair pathway choice. Our review of the literature suggests an alternative view. We propose that 53BP1 has evolved to avoid mutagenic repair outcomes and does so by controlling the processing of DNA ends and the dynamics of DSBs. The consequences of 53BP1 deficiency, such as diminished PARPi efficacy in BRCA1-deficient cells and altered repair of damaged telomeres, can be explained from this viewpoint. We further propose that some of the fidelity functions of 53BP1 coevolved with class switch recombination (CSR) in the immune system. We speculate that, rather than being deterministic in DSB repair pathway choice, 53BP1 functions as a DSB escort that guards against illegitimate and potentially tumorigenic recombination.

53BP1 是一种神秘的 DNA 损伤反应因子，因其决定了 BRCA1 缺陷型癌症中 PARP1 抑制药物（PARPi）的疗效而备受关注。最近的研究将 53BP1 从其作为（又一个）DNA 损伤因子的适度地位提升为双链断裂（DSB）修复途径选择的主要调控因子。我们对文献的回顾提出了另一种观点。我们提出，53BP1 已经进化到避免产生突变的修复结果，其通过控制 DNA 末端的处理和 DSB 的动态来实现这一点。从这个角度来看，可以解释 53BP1 缺乏的后果，例如 BRCA1 缺陷型细胞中 PARPi 疗效降低以及受损端粒的修复改变。我们进一步提出，53BP1 的一些保真功能与免疫系统中的类别转换重组（CSR）共同进化。我们推测，53BP1 在 DSB 修复途径选择中不是决定性的，而是作为 DSB 护航因子，防止不合法且潜在致癌的重组。