LC3B drives transcription-associated homologous recombination via direct interaction with R-loops

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作   者：

Yoon, Junghyun;  Hwang, Yiseul;  Yun, Hansol;  Chung, Jee Min;  Kim, Soyeon;  Kim, Gyeongmin;  Lee, Yeji;  Lee, Byoung Dae;  Kang, Ho Chul; 

作者机构：

Ajou Univ;  Ajou University Department of Physiology; 

关键词：

STRAND BREAK REPAIR;  INSTABILITY;  MECHANISM;  UBIQUITIN;  DNA-DAMAGE;  AUTOPHAGY;  BRCA1; 

期刊名称：

Nucleic Acids Research

i s s n：

0305-1048

年卷期：

2024 年 52 卷 9 期

页   码：

5088-5106

页   码：

摘   要：

Exploring the connection between ubiquitin-like modifiers (ULMs) and the DNA damage response (DDR), we employed several advanced DNA damage and repair assay techniques and identified a crucial role for LC3B. Notably, its RNA recognition motif (RRM) plays a pivotal role in the context of transcription-associated homologous recombination (HR) repair (TA-HRR), a particular subset of HRR pathways. Surprisingly, independent of autophagy flux, LC3B interacts directly with R-loops at DNA lesions within transcriptionally active sites via its RRM, promoting TA-HRR. Using native RNA immunoprecipitation (nRIP) coupled with high-throughput sequencing (nRIP-seq), we discovered that LC3B also directly interacts with the 3 ' UTR AU-rich elements (AREs) of BRCA1 via its RRM, influencing its stability. This suggests that LC3B regulates TA-HRR both proximal to and distal from DNA lesions. Data from our LC3B depletion experiments showed that LC3B knockdown disrupts end-resection for TA-HRR, redirecting it towards the non-homologous end joining (NHEJ) pathway and leading to chromosomal instability, as evidenced by alterations in sister chromatid exchange (SCE) and interchromosomal fusion (ICF). Thus, our findings unveil autophagy-independent functions of LC3B in DNA damage and repair pathways, highlighting its importance. This could reshape our understanding of TA-HRR and the interaction between autophagy and DDR.