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RNaseH2A Downregulation Drives Chromosomal DNA Fragmentation and Accumulation of RNA-DNA Hybrids in Senescent Cells

66 Pages Posted: 18 May 2020 Sneak Peek Status: Under Review

See all articles by Ryo Okada

Ryo Okada

Japanese Foundation for Cancer Research - Project for Cellular Senescence

Sho Sugawara

Japanese Foundation for Cancer Research - Project for Cellular Senescence

Tze Mun Loo

Japanese Foundation for Cancer Research - Project for Cellular Senescence

Kenichi Miyata

Japanese Foundation for Cancer Research - Project for Cellular Senescence

Kaoru Kato

National Institute of Advanced Industrial Science and Technology (AIST) - Health Research Institute

Shizuo Kaji

Kyushu University - 4Institute of Mathematics for Industry

Yoshiro Maezawa

Chiba University - Division of Diabetes, Metabolism and Endocrinology; Chiba University - Department of Clinical Cell Biology and Medicine

Koutaro Yokote

Chiba University - Division of Diabetes, Metabolism and Endocrinology; Chiba University - Department of Clinical Cell Biology and Medicine

Mizuho Nakayama

Kanazawa University - Division of Genetics

Masanobu Oshima

Kanazawa University - Division of Genetics

Koji Nagao

Osaka University - Laboratory of Genome Structure and Function

Chikashi Obuse

Osaka University - Laboratory of Genome Structure and Function

Satoshi Nagayama

Japanese Foundation for Cancer Research - Department of Gastroenterological Surgery

Keiyo Takubo

National Center for Global Health and Medicine - Department of Stem Cell Biology

Akira Nakanishi

Tokyo Medical and Dental University (TMDU) - Department of Molecular Genetics

Glen N. Barber

University of Miami - Department of Medicine

Masato T. Kanemaki

Japan Science and Technology Agency (JST) - Precursory Research for Embryonic Science and Technology (PRESTO)

Eiji Hara

Osaka University - Department of Molecular Microbiology

Akiko Takahashi

Japanese Foundation for Cancer Research

More...

Abstract

Cellular senescence caused by oncogenic stimuli is related to the development of various age-related diseases via senescence-associated secretory phenotype (SASP). Recent studies have revealed that the SASP is induced via the cGAS-STING (cyclic GMP-AMP synthase linked to stimulator of interferon genes) pathway. However, the molecular mechanism of nucleotide ligand production for these cytoplasmic sensors remains unclear. Here, we discover that the expression of RNaseH2A is regulated by E2F transcription factor and decreases during cellular senescence, thus abnormally incorporated ribonucleoside monophosphates (rNMPs) cause genomic DNA fragmentation, while excess R-loop structures lead to RNA-DNA hybrid accumulation in the nucleoli and cytoplasm of senescent cells. Consequently, both chromosomal DNA fragments and RNA-DNA hybrids induce aberrant activation of the cGAS-STING pathway and SASP-factor gene expression. Furthermore, RNaseH2A reduction was associated with pathological features and poor prognoses in individuals with Werner syndrome and cervical, ovarian and colorectal cancers. Our findings provide new insights into how nucleotide ligand production relates to SASP induction.

Keywords: RNaseH2A, rNMPs, RNA-DNA hybrid, genomic DNA fragments, SASP, Werner syndrome, cancer

Suggested Citation

Okada, Ryo and Sugawara, Sho and Loo, Tze Mun and Miyata, Kenichi and Kato, Kaoru and Kaji, Shizuo and Maezawa, Yoshiro and Yokote, Koutaro and Nakayama, Mizuho and Oshima, Masanobu and Nagao, Koji and Obuse, Chikashi and Nagayama, Satoshi and Takubo, Keiyo and Nakanishi, Akira and Barber, Glen N. and Kanemaki, Masato T. and Hara, Eiji and Takahashi, Akiko, RNaseH2A Downregulation Drives Chromosomal DNA Fragmentation and Accumulation of RNA-DNA Hybrids in Senescent Cells. Available at SSRN: https://ssrn.com/abstract=3588831 or http://dx.doi.org/10.2139/ssrn.3588831
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Ryo Okada

Japanese Foundation for Cancer Research - Project for Cellular Senescence ( email )

Japan

Sho Sugawara

Japanese Foundation for Cancer Research - Project for Cellular Senescence ( email )

Japan

Tze Mun Loo

Japanese Foundation for Cancer Research - Project for Cellular Senescence ( email )

Japan

Kenichi Miyata

Japanese Foundation for Cancer Research - Project for Cellular Senescence

Japan

Kaoru Kato

National Institute of Advanced Industrial Science and Technology (AIST) - Health Research Institute ( email )

1-3-1 Kasumigaseki
Chiyoda-ku
Tokyo, 100-8921
Japan

Shizuo Kaji

Kyushu University - 4Institute of Mathematics for Industry ( email )

6-19-1, Hakozaki, Higashiku
Fukuoka, 812-8581
Japan

Yoshiro Maezawa

Chiba University - Division of Diabetes, Metabolism and Endocrinology

1-8-1 Inohana
Chuo-ku, Chiba City
Chiba, 260-8677
Japan

Chiba University - Department of Clinical Cell Biology and Medicine

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Koutaro Yokote

Chiba University - Division of Diabetes, Metabolism and Endocrinology ( email )

1-8-1 Inohana
Chuo-ku, Chiba City
Chiba, 260-8677
Japan

Chiba University - Department of Clinical Cell Biology and Medicine ( email )

1-8-1 Inohana
Chuo-ku
Chiba City, Chiba 260-8670
Japan

Mizuho Nakayama

Kanazawa University - Division of Genetics ( email )

Kanazawa
Japan

Masanobu Oshima

Kanazawa University - Division of Genetics ( email )

Kanazawa
Japan

Koji Nagao

Osaka University - Laboratory of Genome Structure and Function ( email )

1-1 Yamadaoka
Suita
Osaka, 565-0871
Japan

Chikashi Obuse

Osaka University - Laboratory of Genome Structure and Function ( email )

1-1 Yamadaoka
Suita
Osaka, 565-0871
Japan

Satoshi Nagayama

Japanese Foundation for Cancer Research - Department of Gastroenterological Surgery

3-8-31, Ariake, Koto
Tokyo, 135-8550
Japan

Keiyo Takubo

National Center for Global Health and Medicine - Department of Stem Cell Biology ( email )

Tokyo 162-8655
Japan

Akira Nakanishi

Tokyo Medical and Dental University (TMDU) - Department of Molecular Genetics ( email )

1-5-45 Yushima
Bunkyo-ku
Tokyo, 1138519
Japan

Glen N. Barber

University of Miami - Department of Medicine ( email )

Coral Gables, FL 33124
United States

Masato T. Kanemaki

Japan Science and Technology Agency (JST) - Precursory Research for Embryonic Science and Technology (PRESTO)

Saitama
Japan

Eiji Hara

Osaka University - Department of Molecular Microbiology ( email )

1-1 Yamadaoka
Suita
Osaka, 565-0871
Japan

Akiko Takahashi (Contact Author)

Japanese Foundation for Cancer Research

3-8-31, Ariake, Koto
Tokyo, 135-8550
Japan

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