The Cockayne syndrome protein B is involved in the repair of 5-AZA-2′-deoxycytidine-induced DNA lesions

Burgos-Morón, Estefanía; Calderón-Montaño, José Manuel; Pastor, Nuria; Höglund, Andreas; Ruiz-Castizo, Ángel; Domı́nguez, I.; López‐Lázaro, Miguel; Hajji, Nabil; Helleday, Thomas; Mateos, Santiago; Orta, Manuel Luís

doi:10.18632/oncotarget.26189

Cited by 5 publications

(8 citation statements)

References 55 publications

(66 reference statements)

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“…Similarly, treatment with aphidicolin reduces chromosome damage following exposure to 5-azadC, an inhibitor of DNA methyltransferase 1 (DNMT1), suggesting that trapping of DNMT1 at replication forks leads to replication fork collapse [ 136 ]. Increased levels of DNA damage have been observed in CSB-deficient cells exposed to 5-azadC, which is thought to be due to a failure in CSB-mediated TC-NER, leading to increased replication stress [ 64 ]. The synergistic sensitivity observed in a panel of acute myeloid leukemia (AML) cells exposed to olaparib and 5-azadC has been ascribed to a failure to repair the 5-azadC-induced lesions through BER [ 137 ], which could also be a mechanism behind the sensitivity of CSB-deficient cells to this drug since CSB also plays a role in BER.…”

Section: Csb and Its Implications In Targeted Therapy In Cancermentioning

confidence: 99%

Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy

Walker

Zhu

2022

IJMS

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A variety of endogenous and exogenous insults are capable of impeding replication fork progression, leading to replication stress. Several SNF2 fork remodelers have been shown to play critical roles in resolving this replication stress, utilizing different pathways dependent upon the nature of the DNA lesion, location on the DNA, and the stage of the cell cycle, to complete DNA replication in a manner preserving genetic integrity. Under certain conditions, however, the attempted repair may lead to additional genetic instability. Cockayne syndrome group B (CSB) protein, a SNF2 chromatin remodeler best known for its role in transcription-coupled nucleotide excision repair, has recently been shown to catalyze fork reversal, a pathway that can provide stability of stalled forks and allow resumption of DNA synthesis without chromosome breakage. Prolonged stalling of replication forks may collapse to give rise to DNA double-strand breaks, which are preferentially repaired by homology-directed recombination. CSB plays a role in repairing collapsed forks by promoting break-induced replication in S phase and early mitosis. In this review, we discuss roles of CSB in regulating the sources of replication stress, replication stress response, as well as the implications of CSB for cancer therapy.

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Section: Csb and Its Implications In Targeted Therapy In Cancermentioning

confidence: 99%

Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy

Walker

Zhu

2022

IJMS

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“…Although initially surprising, the ability of single agent 5-aza-dC to induce PARP1-DNA adducts is readily explained in the context of the known activities of 5-aza-dC, DNMT1 and PARP1. Incorporation of 5-aza-dC can induce DNA damage, either directly or as a result of aberrant repair of the normally transient covalent DNA adducts formed by DNMT1 (Juttermann et al, 1994;Jackson-Grusby et al, 1997;Palii et al, 2008;Maslov et al, 2012;Orta et al, 2013;Orta et al, 2014;Jeltsch and Jurkowska, 2016;Burgos-Moron et al, 2018). Depletion of DNMT1 protected K562 and GM369 cells from 5-aza-dC, indicating that DNMT1 adducts contribute significantly to 5-aza-dC cytotoxicity in both cell types.…”

Section: Discussionmentioning

confidence: 99%

“…DNA damage results from 5-aza-dC treatment, as evidenced by mutations and genomic instability in surviving cells (Juttermann et al, 1994;Jackson-Grusby et al, 1997;Palii et al, 2008;Maslov et al, 2012;Orta et al, 2013;Orta et al, 2014;Burgos-Moron et al, 2018). A multiprotein complex including not only DNMT1 but also PARP1 responds to damage requiring replicative repair (O'Hagan et al, 2011;Muvarak et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Treatment of human cells with 5-aza-dC induces formation of PARP1-DNA covalent adducts at genomic regions targeted by DNMT1

Kiianitsa

Maizels

2019

Preprint

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5-aza-dC (5-aza-2'-deoxycytidine, clinically known as decitabine) is used to treat some hematopoietic malignancies, but its mechanism of action is not defined. Here we identify a role for covalent PARP1-DNA adducts in cell killing by 5-aza-dC. We demonstrate that covalent PARP1-DNA adducts can be recovered from cells treated with 5-aza-dC alone or in combination with a PARP catalytic inhibitor. PARP1-DNA adducts are predominately 89 kD in length, contain the cleaved PARP1 fragment that is a signature of apoptotic cells, and bear the terminal neo-epitope generated by caspase cleavage. Smaller PARP1-DNA adducts bearing the apoptotic neo-epitope were also detected, but not adducts containing full-length PARP1. DNA-adducted PARP1 fragments thus provide a biochemical link between drug-induced PARP1-DNA adduct formation and cell killing. They support a model in which 5-aza-dC causes DNA damage that recruits fulllength PARP1, which forms covalent adducts that induce apoptosis, resulting in PARP1 cleavage and cell killing.

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“…DNMT1-DPCs could cause the block of DNA replication forks, leading to SSBs and DSBs that provoke cell death if not repaired . Recent studies have revealed a Cockayne syndrome protein B (CSB)-dependent transcription-coupled nucleotide excision repair (TC-NER) pathway to repair 5-azadC-induced DNMT1-DPCs . However, it is unclear if TC-NER is the sole mechanism to remove DNMT1-DPCs or other repair pathways are also involved.…”

Section: Introductionmentioning

confidence: 99%

“…23 Recent studies have revealed a Cockayne syndrome protein B (CSB)-dependent transcription-coupled nucleotide excision repair (TC-NER) pathway to repair 5-azadC-induced DNMT1-DPCs. 24 However, it is unclear if TC-NER is the sole mechanism to remove DNMT1-DPCs or other repair pathways are also involved. In addition, the details of the proteolytic process in the repair of DNMT1-DPCs, which is believed to be the universal step to initiate DPC-repair, have not yet been clarified.…”

Section: ■ Introductionmentioning

confidence: 99%

SPRTN and TDP1/TDP2 Independently Suppress 5-Aza-2′-deoxycytidine-Induced Genomic Instability in Human TK6 Cell Line

Nakano

Moriwaki

Tsuda

et al. 2022

Chem. Res. Toxicol.

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DNA-protein cross-links (DPCs) are generated by internal factors such as cellular aldehydes that are generated during normal metabolism and external factors such as environmental mutagens. A nucleoside analog, 5-aza-2′-deoxycytidine (5-azadC), is randomly incorporated into the genome during DNA replication and binds DNA methyltransferase 1 (DNMT1) covalently to form DNMT1-DPCs without inducing DNA strand breaks. Despite the recent progress in understanding the mechanisms of DPCs repair, how DNMT1-DPCs are repaired is unclear. The metalloprotease SPRTN has been considered as the primary enzyme to degrade protein components of DPCs to initiate the repair of DPCs. In this study, we showed that SPRTN-deficient (SPRTN –/– ) human TK6 cells displayed high sensitivity to 5-azadC, and the removal of 5-azadC-induced DNMT1-DPCs was significantly slower in SPRTN –/– cells than that in wild-type cells. We also showed that the ubiquitination-dependent proteasomal degradation, which was independent of the SPRTN-mediated processing, was also involved in the repair of DNMT1-DPCs. Unexpectedly, we found that cells that are double deficient in tyrosyl DNA phosphodiesterase 1 and 2 (TDP1 –/– TDP2 –/– ) were also sensitive to 5-azadC, although the removal of 5-azadC-induced DNMT1-DPCs was not compromised significantly. Furthermore, the 5-azadC treatment induced a marked accumulation of chromosomal breaks in SPRTN –/– as well as TDP1 –/– TDP2 –/– cells compared to wild-type cells, strongly suggesting that the 5-azadC-induced cell death was attributed to chromosomal DNMT1-DPCs. We conclude that SPRTN protects cells from 5-azadC-induced DNMT1-DPCs, and SPRTN may play a direct proteolytic role against DNMT1-DPCs and TDP1/TDP2 also contributes to suppress genome instability caused by 5-azadC in TK6 cells.

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The Cockayne syndrome protein B is involved in the repair of 5-AZA-2′-deoxycytidine-induced DNA lesions

Cited by 5 publications

References 55 publications

Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy

Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy

Treatment of human cells with 5-aza-dC induces formation of PARP1-DNA covalent adducts at genomic regions targeted by DNMT1

SPRTN and TDP1/TDP2 Independently Suppress 5-Aza-2′-deoxycytidine-Induced Genomic Instability in Human TK6 Cell Line

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