Base-excision repair pathway regulates transcription-replication conflicts in pancreatic ductal adenocarcinoma.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2024-10-22 Epub Date: 2024-10-04 DOI:10.1016/j.celrep.2024.114820

Fan Meng, Tiane Li, Anup K Singh, Yingying Wang, Marc Attiyeh, Fatemeh Kohram, Qianhua Feng, Yun R Li, Binghui Shen, Terence Williams, Yilun Liu, Mustafa Raoof

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Abstract

Oncogenic mutations (such as in KRAS) can dysregulate transcription and replication, leading to transcription-replication conflicts (TRCs). Here, we demonstrate that TRCs are enriched in human pancreatic ductal adenocarcinoma (PDAC) compared to other common solid tumors or normal cells. Several orthogonal approaches demonstrated that TRCs are oncogene dependent. A small interfering RNA (siRNA) screen identified several factors in the base-excision repair (BER) pathway as main regulators of TRCs in PDAC cells. Inhibitors of BER pathway (methoxyamine and CRT) enhanced TRCs. Mechanistically, BER pathway inhibition severely altered RNA polymerase II (RNAPII) and R-loop dynamics at nascent DNA, causing RNAPII trapping and contributing to enhanced TRCs. The ensuing DNA damage activated the ATR-Chk1 pathway. Co-treatment with ATR inhibitor (VX970) and BER inhibitor (methoxyamine) at clinically relevant doses synergistically enhanced DNA damage and reduced cell proliferation in PDAC cells. The study provides mechanistic insights into the regulation of TRCs in PDAC by the BER pathway, which has biologic and therapeutic implications.

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碱基切除修复途径调节胰腺导管腺癌的转录-复制冲突

致癌突变（如 KRAS）可导致转录和复制失调，从而导致转录-复制冲突（TRC）。在这里，我们证明与其他常见实体瘤或正常细胞相比，TRCs 在人类胰腺导管腺癌（PDAC）中富集。几种正交方法证明 TRCs 依赖于癌基因。一项小干扰 RNA（siRNA）筛选发现，碱基切除修复（BER）通路中的几个因子是 PDAC 细胞中 TRCs 的主要调节因子。BER途径抑制剂（甲氧基胺和CRT）增强了TRCs。从机理上讲，BER途径抑制严重改变了新生DNA上的RNA聚合酶II（RNAPII）和R环的动力学，导致RNAPII被困，从而增强了TRCs。随之而来的DNA损伤激活了ATR-Chk1通路。临床相关剂量的ATR抑制剂（VX970）和BER抑制剂（甲氧基胺）联合治疗可协同增强PDAC细胞的DNA损伤并减少细胞增殖。这项研究从机理上揭示了 BER 通路对 PDAC 中 TRC 的调控，具有生物学和治疗学意义。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.