San1 deficiency leads to cardiomyopathy due to excessive R-loop-associated DNA damage and cardiomyocyte hypoplasia.
San1 deficiency leads to cardiomyopathy due to excessive R-loop-associated DNA damage and cardiomyocyte hypoplasia.
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DOI：
10.1016/j.bbadis.2021.166237
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发表时间：
2021-11-01
期刊：
影响因子：
--
通讯作者：
Long Q
中科院分区：
文献类型：
--
作者：
Liu Z;Gao X;Zhou Z;Kang SW;Yang Y;Liu H;Zhang C;Wen Z;Rao X;Wang D;White D 3rd;Yang Q;Long Q
R环是含有RNA/DNA杂合体的天然存在的转录中间体。过多的R环会导致基因组不稳定、DNA损伤和复制应激。Senataxin-associated exonuclease（San 1）是一种与Senataxin（SETX）相互作用的蛋白质，SETX是一种解旋酶，可解析R环。目前尚不清楚R环诱导的DNA损伤是否在心脏中起作用，特别是在增殖的新生儿心肌细胞（CM）中。使用CRISPR/Cas9技术产生San 1 −/−小鼠。新生的San 1 −/−小鼠没有表现出明显的表型，但它们的心脏更小，CM更大，但更少。CM增殖受损，细胞周期相关的转录本和蛋白质减少。S9.6染色显示新生San 1 −/− CM细胞核中积累了过量的R环。新生儿和成人心脏切片上γ H2 AX染色增加显示DNA损伤增加。类似地，San 1 −/− AC 16-心肌细胞显示累积的R环和DNA损伤，导致细胞周期检查点激酶ATR和PARP 1过度活化，阻止G2/M细胞周期和CM增殖。总之，本研究揭示了San 1在解决导致DNA损伤和抑制CM增殖的过度R环中的重要作用，为San 1在新生儿心脏中的新生物学功能提供了新的见解。San 1可能成为治疗发育不良性心脏疾病的新靶点。
R-loops are naturally occurring transcriptional intermediates containing RNA/DNA hybrids. Excessive R-loops cause genomic instability, DNA damage, and replication stress. Senataxin-associated exonuclease (San1) is a protein that interacts with Senataxin (SETX), a helicase resolving R-loops. It remains unknown if R-loops-induced DNA damage plays a role in the heart, especially in the proliferative neonatal cardiomyocytes (CMs). San1−/− mice were generated using the CRISPR/Cas9 technique. The newborn San1−/− mice show no overt phenotype, but their hearts were smaller with larger, yet fewer CMs. CM proliferation was impaired with reduced cell cycle-related transcripts and proteins. S9.6 staining revealed that excessive R-loops accumulated in the nucleus of neonatal San1−/− CMs. Increased γH2AX staining on newborn and adult heart sections exhibited increased DNA damage. Similarly, San1−/− AC16-cardiomyocytes showed cumulative R-loops and DNA damage, leading to the activation of cell cycle checkpoint kinase ATR and PARP1 hyperactivity, arresting G2/M cell-cycle and CM proliferation. Together, the present study uncovers an essential role of San1 in resolving excessive R-loops that lead to DNA damage and repressing CM proliferation, providing new insights into a novel biological function of San1 in the neonatal heart. San1 may serve as a novel therapeutic target for the treatment of hypoplastic cardiac disorders.
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影响因子：
4.5
作者：
Morales JC;Richard P;Patidar PL;Motea EA;Dang TT;Manley JL;Boothman DA
通讯作者：
Boothman DA
影响因子：
16
作者：
Krishnakumar R;Kraus WL
通讯作者：
Kraus WL
DOI：
10.1007/978-3-319-89689-2_10
发表时间：
2018-01-01
期刊：
RNA METABOLISM IN NEURODEGENERATIVE DISEASES
影响因子：
--
作者：
Bennett, Craig L.;La Spada, Albert R.
通讯作者：
La Spada, Albert R.
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影响因子：
16
作者：
Ginno PA;Lott PL;Christensen HC;Korf I;Chédin F
通讯作者：
Chédin F
影响因子：
16.6
作者：
Cohen S;Puget N;Lin YL;Clouaire T;Aguirrebengoa M;Rocher V;Pasero P;Canitrot Y;Legube G
通讯作者：
Legube G