通过 MMEJ（替代 NHEJ）的 HDR
中文名称
通路描述
同源定向修复（HDR）通过微同源介导的末端连接（MMEJ）是一种易出错的过程，也称为替代非同源末端连接（alt-NHEJ）。尽管它不涉及参与经典 NHEJ 的蛋白质，但与经典 NHEJ 和其他 HDR 途径不同，同源重组修复（HRR）和单链退火（SSA）并不要求 ATM 激活。事实上，ATM 激活会抑制 MMEJ。因此，当 DNA 双链断裂（DSBs）的数量超过高保真 DNA 修复机器的能力，或者细胞缺乏高保真 DNA 修复成分时，MMEJ 可能会被触发。MMEJ 由 MRN 复合物（MRE11A:RAD50:NBN）和 RBBP8（CtIP）在 CDK2 介导的 RBBP8 磷酸化缺失以及 BRCA1:BARD1 招募缺失的情况下，对 DNA DSB 末端进行有限切除来启动。单链 DNA（ssDNA）在切除的 DNA DSB 末端招募 PARP1 或 PARP2 同源二聚体，以及 DNA 聚合酶 theta（POLQ）和 FEN1 5'-末端核酸酶。在尚未完全研究的序列事件中，POLQ 促进两个 3'-ssDNA 突出物通过微同源区域进行配对，这些微同源区域的最优长度为 10-19 个核苷酸。利用与 POLB 介导的长补丁碱基切除修复（BER）的类比，PARP1（或 PARP2）二聚体通过 POLQ 介导的链置换合成与 FEN1 介导的 5'-末端切除协调延伸配对后的 3'-ssDNA 突出物。MRN 复合物随后招募与 XRCC1 结合的 DNA 连接酶 3（LIG3）来连接 MMEJ 位点的剩余单链缺口（SSBs）。与单链退火（SSA）类似，MMEJ 会导致使用配对作为退火微同源区域之一的微同源区域的删除，以及两个配对微同源区域之间的 DNA 序列。MMEJ 就像经典 NHEJ 一样，可能导致基因组易位。此外，由于 POLQ 是一种易错 DNA 聚合酶，MMEJ 会引入频繁的碱基替换。
英文描述
NOTCH2 intracellular domain regulates transcription In the nucleus, NICD2 forms a complex with RBPJ (CBF1, CSL) and MAML (mastermind). NICD2:RBPJ:MAML complex activates transcription from RBPJ-binding promoter elements (RBEs) (Wu et al. 2000). Besides NICD2, RBPJ and MAML, NOTCH2 coactivator complex likely includes other proteins, shown as components of the NOTCH1 coactivator complex.
NOTCH2 coactivator complex directly stimulates transcription of HES1 and HES5 genes (Shimizu et al. 2002), both of which are known NOTCH1 targets.
The promoter of FCER2 (CD23A) contains several RBEs that are occupied by NOTCH2 but not NOTCH1 coactivator complexes, and NOTCH2 activation stimulates FCER2 transcription. Overexpression of FCER2 (CD23A) is a hallmark of B-cell chronic lymphocytic leukemia (B-CLL) and correlates with the malfunction of apoptosis, which is thought be an underlying mechanism of B-CLL development. The Epstein-Barr virus protein EBNA2 can also activate FCER2 transcription through RBEs, possibly by mimicking NOTCH2 signaling (Hubmann et al. 2002).
NOTCH2 coactivator complex occupies the proximal RBE of the GZMB (granzyme B) promoter and at the same time interacts with phosphorylated CREB1, bound to an adjacent CRE site. EP300 transcriptional coactivator is also recruited to this complex through association with CREB1 (Maekawa et al. 2008). NOTCH2 coactivator complex together with CREBP1 and EP300 stimulates transcription of GZMB (granzyme B), which is important for the cytotoxic function of CD8+ T-cells (Maekawa et al. 2008).
There are indications that NOTCH2 genetically interacts with hepatocyte nuclear factor 1-beta (HNF1B) in kidney development (Massa et al. 2013, Heliot et al. 2013) and with hepatocyte nuclear factor 6 (HNF6) in bile duct formation (Vanderpool et al. 2012), but the exact nature of these genetic interactions has not been defined.
NOTCH2 coactivator complex directly stimulates transcription of HES1 and HES5 genes (Shimizu et al. 2002), both of which are known NOTCH1 targets.
The promoter of FCER2 (CD23A) contains several RBEs that are occupied by NOTCH2 but not NOTCH1 coactivator complexes, and NOTCH2 activation stimulates FCER2 transcription. Overexpression of FCER2 (CD23A) is a hallmark of B-cell chronic lymphocytic leukemia (B-CLL) and correlates with the malfunction of apoptosis, which is thought be an underlying mechanism of B-CLL development. The Epstein-Barr virus protein EBNA2 can also activate FCER2 transcription through RBEs, possibly by mimicking NOTCH2 signaling (Hubmann et al. 2002).
NOTCH2 coactivator complex occupies the proximal RBE of the GZMB (granzyme B) promoter and at the same time interacts with phosphorylated CREB1, bound to an adjacent CRE site. EP300 transcriptional coactivator is also recruited to this complex through association with CREB1 (Maekawa et al. 2008). NOTCH2 coactivator complex together with CREBP1 and EP300 stimulates transcription of GZMB (granzyme B), which is important for the cytotoxic function of CD8+ T-cells (Maekawa et al. 2008).
There are indications that NOTCH2 genetically interacts with hepatocyte nuclear factor 1-beta (HNF1B) in kidney development (Massa et al. 2013, Heliot et al. 2013) and with hepatocyte nuclear factor 6 (HNF6) in bile duct formation (Vanderpool et al. 2012), but the exact nature of these genetic interactions has not been defined.
所含基因
12 个基因