Lodovichi Samuele, Nepomuceno Thales C, Woods Nicholas T, Rix Uwe, Koomen John M, Pellicioli Achille, Galli Alvaro, Monteiro Alvaro N A
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Yeast Genetics and Genomics, Laboratory of Functional Genetics and Genomics, Institute of Clinical Physiology, CNR, 56125 Pisa, Italy.
iScience. 2024 Oct 24;27(11):111252. doi: 10.1016/j.isci.2024.111252. eCollection 2024 Nov 15.
PARP1 inhibitors (PARPis) are used for treatment of cancers with mutations in or that are deficient in homologous recombination. The identification of modulators of PARP1 activity is critical to understand and overcome resistance to PARPis. We integrated data from three omics-scale screens to discover new regulators of PARP1 activity. We identified SART1 and show that its silencing leads to an increase in poly-ADP ribosylation and chromatin-bound PARP1. SART1 is recruited to chromatin following DNA damage and limits PARP1 chromatin retention and activity. The SART1 N-terminus is sufficient to regulate the accumulation of PAR chains and PARP1 on chromatin, an activity dependent on the RGG/RG box. Silencing of SART1 leads to an increased sensitivity of cells to DNA damage induced by IR, irrespective of status and to PARPis only in absence of . These results suggest that SART1 could be clinically utilized to improve PARPi efficacy.
聚（ADP - 核糖）聚合酶1抑制剂（PARP1抑制剂）用于治疗在同源重组方面存在突变或缺陷的癌症。鉴定PARP1活性调节剂对于理解和克服对PARP1抑制剂的耐药性至关重要。我们整合了来自三个组学规模筛选的数据，以发现PARP1活性的新调节剂。我们鉴定出SART1，并表明其沉默会导致多聚ADP核糖基化和与染色质结合的PARP1增加。DNA损伤后，SART1被招募到染色质上，并限制PARP1在染色质上的保留和活性。SART1的N末端足以调节PAR链和PARP1在染色质上的积累，这种活性依赖于RGG/RG框。SART1的沉默导致细胞对IR诱导的DNA损伤的敏感性增加，无论BRCA状态如何，并且仅在缺乏BRCA时对PARP1抑制剂敏感。这些结果表明，SART1可在临床上用于提高PARP1抑制剂的疗效。
