Semenova Svetlana A, Nammi Deepthi, Garrett Grace A, Margolin Gennady, Sinclair Jennifer L, Maroofian Reza, Caldecott Keith W, Burgess Harold A
Division of Developmental Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
Bioinformatics and Scientific Programming Core, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892, USA.
bioRxiv. 2024 Nov 25:2024.11.25.625242. doi: 10.1101/2024.11.25.625242.
Defects in DNA single-strand break repair are associated with neurodevelopmental and neurodegenerative disorders. One such disorder is that resulting from mutations in , a scaffold protein that plays a central role in DNA single-strand base repair. XRCC1 is recruited at sites of single-strand breaks by PARP1, a protein that detects and is activated by such breaks and is negatively regulated by XRCC1 to prevent excessive PARP binding and activity. Loss of XRCC1 leads to the toxic accumulation and activity of PARP1 at single-strand breaks leading to base excision repair defects, a mechanism that may underlie pathological changes in patients carrying deleterious mutations. Here, we demonstrate that knockdown impairs development of the cerebellar plate in zebrafish. In contrast, knockdown alone does not significantly affect neural development, and instead rescues the cerebellar defects observed in mutant larvae. These findings support the notion that PARP1 inhibition may be a viable therapeutic candidate in neurological disorders.
DNA单链断裂修复缺陷与神经发育和神经退行性疾病有关。其中一种疾病是由 基因突变引起的，该基因是一种支架蛋白，在DNA单链碱基修复中起核心作用。XRCC1由PARP1招募到单链断裂位点，PARP1是一种能检测此类断裂并被其激活的蛋白质，且受XRCC1负调控以防止PARP过度结合和活性过高。XRCC1的缺失会导致PARP1在单链断裂处的毒性积累和活性增加，从而导致碱基切除修复缺陷，这一机制可能是携带有害 基因突变患者病理变化的基础。在此，我们证明在斑马鱼中敲低 会损害小脑板的发育。相比之下，单独敲低 不会显著影响神经发育，反而能挽救在 突变幼虫中观察到的小脑缺陷。这些发现支持了PARP1抑制可能是神经疾病中一种可行治疗方法的观点。
