由于 PALB2 失去与 BRCA1 结合功能导致的同源重组修复 (HRR) 缺陷
中文名称
通路描述
PALB2 N 端螺旋结构域（氨基酸 9-44）的突变，涉及自相互作用和与 BRCA1 的结合，导致 PALB2 与 BRCA1 的相互作用受损（Sy et al. 2009, Foo et al. 2017, Boonen et al. 2020）。ATR 对 PALB2 的磷酸化（丝氨酸残基 S59）促进 PALB2 与 BRCA1 的结合以及 PALB2 向 DNA 损伤位点的定位（Buisson et al. 2017）。螺旋结构域中的突变也会影响 PALB2 的自相互作用、招募至双链断裂位点、同源重组修复以及 RAD51 聚集体形成（Buisson and Masson 2012）。无法与 BRCA1 结合的 PALB2 错义突变体仍可通过与其他参与双链断裂修复的蛋白相互作用被招募至 DNA 双链断裂修复位点，但在 PALB2 缺陷细胞中无法恢复高效的基因转换，并对 DNA 损伤剂米托霉素 C 产生超敏反应（Sy et al. 2009）。该区域的一些变体也对 PARP 抑制剂敏感（Foo et al. 2017）。
英文描述
Regulation of cholesterol biosynthesis by SREBP (SREBF) Sterol regulatory element binding proteins (SREBPs, SREBFs) respond to low cholesterol concentrations by transiting to the nucleus and activating genes involved in cholesterol and lipid biosynthesis (reviewed in Brown and Goldstein 2009, Osborne and Espenshade 2009, Weber et al. 2004).
Newly synthesized SREBPs are transmembrane proteins that bind SCAP in the endoplasmic reticulum (ER) membrane. SCAP binds cholesterol which causes a conformational change that allows SCAP to interact with INSIG, retaining the SCAP:SREBP complex in the ER. INSIG binds oxysterols, which cause INSIG to bind SCAP and retain SCAP:SREBP in the endoplasmic reticulum.
In low cholesterol (below about 5 mol%) SCAP no longer interacts with cholesterol or INSIG and binds Sec24 of the CopII coat complex instead. Thus SCAP:SREBP transits with the CopII complex from the ER to the Golgi. In the Golgi SREBP is cleaved by S1P and then by S2P, releasing the N-terminal fragment of SREBP into the cytosol. The N-terminal fragment is imported to the nucleus by importin-beta and then acts with other factors, such as SP1 and NF-Y, to activate transcription of target genes. Targets of SREBP include the genes encoding all enzymes of cholesterol biosynthesis and several genes involved in lipogenesis. SREBP2 most strongly activates cholesterol biosynthesis while SREBP1C most strongly activates lipogenesis.
Newly synthesized SREBPs are transmembrane proteins that bind SCAP in the endoplasmic reticulum (ER) membrane. SCAP binds cholesterol which causes a conformational change that allows SCAP to interact with INSIG, retaining the SCAP:SREBP complex in the ER. INSIG binds oxysterols, which cause INSIG to bind SCAP and retain SCAP:SREBP in the endoplasmic reticulum.
In low cholesterol (below about 5 mol%) SCAP no longer interacts with cholesterol or INSIG and binds Sec24 of the CopII coat complex instead. Thus SCAP:SREBP transits with the CopII complex from the ER to the Golgi. In the Golgi SREBP is cleaved by S1P and then by S2P, releasing the N-terminal fragment of SREBP into the cytosol. The N-terminal fragment is imported to the nucleus by importin-beta and then acts with other factors, such as SP1 and NF-Y, to activate transcription of target genes. Targets of SREBP include the genes encoding all enzymes of cholesterol biosynthesis and several genes involved in lipogenesis. SREBP2 most strongly activates cholesterol biosynthesis while SREBP1C most strongly activates lipogenesis.
所含基因
14 个基因