Nuclear IMPDH2 controls the DNA damage response by modulating PARP1 activity

Nuclear metabolism and DNA damage response are intertwined processes, but the precise molecular connections remain elusive. Here, we delve into this crosstalk using as a model triple-negative breast cancer (TNBC), a subtype often prone to DNA damage accumulation. We reveal that the de novo purine synthesis enzyme Inosine monophosphate dehydrogenase 2 (IMPDH2) is enriched on chromatin in TNBC when compared to other subtypes. IMPDH2 chromatin localization is DNA damage dependent and IMPDH2 repression leads to DNA damage accumulation. On chromatin, IMPDH2 interacts and modulates Poly [ADP-ribose] polymerase 1 (PARP1) activity by controlling nuclear availability of nicotinamide adenine dinucleotide (NAD+) -a shared metabolic cofactor- to fine-tune the DNA damage response. However, when IMPDH2 is restricted to the nucleus, it depletes nuclear NAD+, leading to PARP1 cleavage and cell death. Our study identifies a non-canonical nuclear role for IMPDH2 that act as convergence point of nuclear metabolism and DNA damage response. # Contributed equally *Corresponding authors: [e-mail]; [e-mail] Overall design: To investigate the role of IMPDH2 in MDA-MB-231 triple-negative breast cancer (TNBC) cell line, IMPDH2 gene was knocked-out and reconstituted in different forms and under different growth conditions.

核代谢与DNA损伤应答是相互交织的生物学过程，但其确切的分子关联仍未明确。本研究以易发生DNA损伤累积的三阴性乳腺癌（triple-negative breast cancer, TNBC）为模型，探究二者之间的交叉调控机制。我们发现，相较于其他乳腺癌亚型，三阴性乳腺癌细胞中嘌呤从头合成酶肌苷单磷酸脱氢酶2（Inosine monophosphate dehydrogenase 2, IMPDH2）在染色质上的富集程度更高。IMPDH2的染色质定位依赖于DNA损伤状态，而抑制IMPDH2会导致DNA损伤累积。在染色质上，IMPDH2可通过调控烟酰胺腺嘌呤二核苷酸（nicotinamide adenine dinucleotide, NAD+，一种共享的代谢辅因子）的核内可用量，与多聚ADP核糖聚合酶1（Poly [ADP-ribose] polymerase 1, PARP1）相互作用并调节其活性，从而精准微调DNA损伤应答过程。但当IMPDH2被限制在细胞核内时，它会消耗细胞核内的NAD+，进而引发PARP1裂解并导致细胞死亡。本研究揭示了IMPDH2一种非经典的核内功能：其可作为核代谢与DNA损伤应答的交汇节点。
# 作者贡献相等
* 通讯作者：[e-mail]; [e-mail]
实验设计：为探究IMPDH2在MDA-MB-231三阴性乳腺癌细胞系中的功能，我们对该细胞系的IMPDH2基因进行敲除，并在不同生长条件下以多种形式对其进行重构。