San1 deficiency leads to cardiomyopathy due to excessive R-loop-associated DNA damage and cardiomyocyte hypoplasia

Liu, Zhiheng; Xu, Genhui; Zhou, Zhou; Kang, Sung Wook; Yong, Yang; Líu, Hao; Zhang, Chunqin; Wen, Zheng; Rao, Xiaoquan; Wang, Daowen; White, Donnell; Yang, Qinglin; Long, Qinqiang

doi:10.1016/j.bbadis.2021.166237

Cited by 7 publications

(3 citation statements)

References 54 publications

(72 reference statements)

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“…Senataxin is posttranslationally modified and its modified forms are marked by asterisks ( 37 , 38 ). Nonspecific bands are seen in other studies ( 39 )). ( B and C ) RNase H1 is recruited to nuclear foci and nucleoli in HPV-positive cells.…”

Section: Resultsmentioning

confidence: 51%

p53-dependent R-loop formation and HPV pathogenesis

Templeton,

Laimins

2023

Proc. Natl. Acad. Sci. U.S.A.

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R-loops are trimeric RNA: DNA hybrids that are important physiological regulators of transcription; however, their aberrant formation or turnover leads to genomic instability and DNA breaks. High-risk human papillomaviruses (HPV) are the causative agents of genital as well as oropharyngeal cancers and exhibit enhanced amounts of DNA breaks. The levels of R-loops were found to be increased up to 50-fold in cells that maintain high-risk HPV genomes and were readily detected in squamous cell cervical carcinomas in vivo but not in normal cells. The high levels of R-loops in HPV-positive cells were present on both viral and cellular sites together with RNase H1, an enzyme that controls their resolution. Depletion of RNase H1 in HPV-positive cells further increased R-loop levels, resulting in impaired viral transcription and replication along with reduced expression of the DNA repair genes such as FANCD2 and ATR, both of which are necessary for viral functions. Overexpression of RNase H1 decreased total R-loop levels, resulting in a reduction of DNA breaks by over 50%. Furthermore, increased RNase H1 expression blocked viral transcription and replication while enhancing the expression of factors in the innate immune regulatory pathway. This suggests that maintaining elevated R-loop levels is important for the HPV life cycle. The E6 viral oncoprotein was found to be responsible for inducing high levels of R-loops by inhibiting p53’s transcriptional activity. Our studies indicate that high R-loop levels are critical for HPV pathogenesis and that this depends on suppressing the p53 pathway.

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Section: Resultsmentioning

confidence: 51%

p53-dependent R-loop formation and HPV pathogenesis

Templeton,

Laimins

2023

Proc. Natl. Acad. Sci. U.S.A.

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“…R-loop persistence in mitosis resulting from depletion of the R-loop resolving helicase senataxin (SETX) has also been shown to induce chromosomal fragility and DNA under-replication 121 . Deficiency in the SETX-interacting factor senataxin-associated exonuclease 1 (San1) induces early onset murine cardiomyopathy associated with elevated cardiomyocyte R-loop and DSB levels, evidencing the role of replication stress-induced DNA damage accrual in premature induction of age-related pathologies 122 .…”

Section: Hallmarks Of Aging Driven By Replication Stressmentioning

confidence: 99%

Replication stress as a driver of cellular senescence and aging

Herr,

Schaffer,

Fuchs

et al. 2024

Commun Biol

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Replication stress refers to slowing or stalling of replication fork progression during DNA synthesis that disrupts faithful copying of the genome. While long considered a nexus for DNA damage, the role of replication stress in aging is under-appreciated. The consequential role of replication stress in promotion of organismal aging phenotypes is evidenced by an extensive list of hereditary accelerated aging disorders marked by molecular defects in factors that promote replication fork progression and operate uniquely in the replication stress response. Additionally, recent studies have revealed cellular pathways and phenotypes elicited by replication stress that align with designated hallmarks of aging. Here we review recent advances demonstrating the role of replication stress as an ultimate driver of cellular senescence and aging. We discuss clinical implications of the intriguing links between cellular senescence and aging including application of senotherapeutic approaches in the context of replication stress.

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“…While substantial progress has been made to uncover the underlying mechanisms and biological role of R-loop formation (reviewed elsewhere in great detail [ 4 , 5 , 6 , 7 , 8 ]), increasing numbers of reports indicate the detrimental consequences of unscheduled RNA formation. For example, aberrant R-loop formation and accumulation has been associated with several human diseases [ 3 , 4 , 5 , 7 , 19 ], such as cancer [ 20 , 21 , 22 ] and neurological [ 23 , 24 ], hematological [ 25 ], and cardiovascular disorders [ 21 , 26 ]. In addition, the initial reports [ 27 , 28 ] indicate a potential role of R-loops as a potent diagnostic biomarker.…”

Section: Introductionmentioning

confidence: 99%

Pathophysiological Role and Diagnostic Potential of R-Loops in Cancer and Beyond

Khan

Danckwardt

2022

Genes

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R-loops are DNA–RNA hybrids that play multifunctional roles in gene regulation, including replication, transcription, transcription–replication collision, epigenetics, and preserving the integrity of the genome. The aberrant formation and accumulation of unscheduled R-loops can disrupt gene expression and damage DNA, thereby causing genome instability. Recent links between unscheduled R-loop accumulation and the abundance of proteins that modulate R-loop biogenesis have been associated with numerous human diseases, including various cancers. Although R-loops are not necessarily causative for all disease entities described to date, they can perpetuate and even exacerbate the initially disease-eliciting pathophysiology, making them structures of interest for molecular diagnostics. In this review, we discuss the (patho) physiological role of R-loops in health and disease, their surprising diagnostic potential, and state-of-the-art techniques for their detection.

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San1 deficiency leads to cardiomyopathy due to excessive R-loop-associated DNA damage and cardiomyocyte hypoplasia

Cited by 7 publications

References 54 publications

p53-dependent R-loop formation and HPV pathogenesis

p53-dependent R-loop formation and HPV pathogenesis

Replication stress as a driver of cellular senescence and aging

Pathophysiological Role and Diagnostic Potential of R-Loops in Cancer and Beyond

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