由于BRCA1功能丧失导致的同源重组修复缺陷
中文名称
通路描述
除了其在DNA双链断裂（DSB）信号传导中的作用外，BRCA1还直接促进招募PALB2和间接招募BRCA2以修复DSB。此外，BRCA1增加了DNA末端切除的速度和过程性，该过程涉及5'至3'核酸酶降解DSB（Cruz-Garcia等，2014）。BRCA1与PALB2的直接相互作用有助于微调BRCA2和RAD51在DSB处的定位（Zhang等，2009；Sy等，2009）。PALB2同时与RAD51、BRCA2和RAD51AP1相互作用（Modesti等，2007；Wiese等，2007；Buisson等，2010；Dray等，2010）。PALB2和RAD51AP1协同刺激RAD51重组酶活性，从而增强RAD51介导的链交换（分支迁移）并促进DSO环结构的形成（突触复合物组装）。当互补双链DNA（姐妹染色单体臂）被RAD51核蛋白丝逐步入侵时，形成DSO环结构，其中入侵ssDNA与互补姐妹染色单体DNA链之间形成碱基配对（Sung等，2003）。BRCA1的N端区域包含RING结构域（残基7-98），对于BRCA1与BARD1的异二聚化是必需的。BRCA1:BARD1异二聚体具有E3泛素连接酶活性，这对于DNA修复至关重要（Drost等，2011）。RING结构域内的几个错义突变已被与患乳腺癌/卵巢癌的风险增加联系起来（Bouwman等，2013；Starita等，2018）。在BARD1结合缺陷的BRCA1突变蛋白中，已将该通路注释为“由于BRCA1功能丧失导致的DNA双链断裂响应缺陷”。BRCA1 C端区域包含两个螺旋线圈结构域（残基1397-1424）和两个BRCT结构域（BRCT 1：残基1642-1736；BRCT 2：残基1756-1855），参与PALB2结合，其中第二个螺旋线圈结构域是必需的（Sy等，2009）。一些影响C端区域的致癌性BRCA1错义突变已被证明具有降低与PALB2结合的能力（Sy等，2009）。此外，癌症报道的BRCA1中许多无义和移码突变导致截短蛋白，缺乏PALB2结合结构域。
英文描述
Defective homologous recombination repair (HRR) due to BRCA1 loss of function In addition to its role in DNA double-strand break (DSB) signaling, BRCA1 plays an important role in homologous recombination repair (HRR) of DSBs by directly promoting recruitment of PALB2 and indirectly BRCA2 to DSB repair sites. In addition, BRCA1 increases the speed and processivity of DNA end resection which consists of 5â²â3â² nucleolytic degradation of DSBs (Cruz-Garcia et al. 2014). The direct BRCA1 interaction with PALB2 helps to fine-tune the localization of BRCA2 and RAD51 at DSBs (Zhang et al. 2009, Sy et al. 2009). PALB2 simultaneously interacts with RAD51, BRCA2 and RAD51AP1 (Modesti et al. 2007, Wiese et al. 2007, Buisson et al. 2010, Dray et al. 2010). PALB2 and RAD51AP1 synergistically stimulate RAD51 recombinase activity, thus enhancing RAD51-mediated strand exchange (branch migration) and promoting the formation of D-loop structures (synaptic complex assembly). A D-loop structure is formed when complementary duplex DNA (sister chromatid arm) is progressively invaded by the RAD51 nucleoprotein filament, with base pairing of the invading ssDNA and the complementary sister chromatid DNA strand (Sung et al. 2003).
The N-terminal region of BRCA1 contains the RING domain (residues 7-98), required for the heterodimerization of BRCA1 with BARD1. BRCA1:BARD1 heterodimer has E3 ubiquitin ligase activity which is important for DNA repair (Drost et al. 2011). Several missense mutations within the RING domain have been linked to increased risks of developing breast/ovarian cancers (Bouwman et al. 2013; Starita et al. 2018). BRCA1 mutant proteins impaired in BARD1 binding are annotated in the pathway "Defective DNA double strand break response due to BRCA1 loss of function".
The C-terminal region of BRCA1 which contains two coiled coil domains (residues 1397-1424) and two BRCT domains (residues 1642-1736 for BRCT 1; residues 1756-1855 for BRCT 2) is involved in PALB2 binding, with the second coiled coil domain being essential (Sy et al. 2009). Several cancer-associated BRCA1 missense mutants that affect the C-terminal region were shown to have reduced ability to bind PALB2 (Sy et al. 2009). In addition, many nonsense and frameshift mutations in BRCA1 reported in cancer result in truncated proteins that lack the PALB2-binding domain.
The N-terminal region of BRCA1 contains the RING domain (residues 7-98), required for the heterodimerization of BRCA1 with BARD1. BRCA1:BARD1 heterodimer has E3 ubiquitin ligase activity which is important for DNA repair (Drost et al. 2011). Several missense mutations within the RING domain have been linked to increased risks of developing breast/ovarian cancers (Bouwman et al. 2013; Starita et al. 2018). BRCA1 mutant proteins impaired in BARD1 binding are annotated in the pathway "Defective DNA double strand break response due to BRCA1 loss of function".
The C-terminal region of BRCA1 which contains two coiled coil domains (residues 1397-1424) and two BRCT domains (residues 1642-1736 for BRCT 1; residues 1756-1855 for BRCT 2) is involved in PALB2 binding, with the second coiled coil domain being essential (Sy et al. 2009). Several cancer-associated BRCA1 missense mutants that affect the C-terminal region were shown to have reduced ability to bind PALB2 (Sy et al. 2009). In addition, many nonsense and frameshift mutations in BRCA1 reported in cancer result in truncated proteins that lack the PALB2-binding domain.
所含基因
23 个基因