The Multiple Cellular Roles of SMUG1 in Genome Maintenance and Cancer

Raja, Sripriya; Houten, Bennett Van

doi:10.3390/ijms22041981

Cited by 13 publications

(4 citation statements)

References 63 publications

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“…Endogenously, hmdU accumulates in genomic DNA through several ways, including loss of the glycosidase DNPH1, which hydrolyzes hmdU, hydroxylation of thymidine by TET dioxygenases, oxidation of thymidine by reactive oxygen species, and deamination of 5-hydroxymethylcytosine (5hmC) by cytidine deaminase (Fugger et al, 2021;Olinski et al, 2016;Pfaffeneder et al, 2014;Teebor et al, 1984). Although not cytotoxic on its own, cells become sensitive to genomic hmdU when the uracil glycosylase SMUG1 hydrolyzes the base to create an abasic site (Fugger et al, 2021;Raja and Van Houten, 2021;Taglialatela et al, 2021) To separate the roles of replication fork protection and ssDNA gap suppression in the response to hmdU, we rescued both pathways by depleting SMARCAL1 and PRIMPOL, respectively. We found that PRIMPOL-mediated gap formation is responsible for hmdU sensitivity and that this was specifically due to gap formation at abasic sites generated by SMUG1.…”

Section: Primpol-dependent Ssdna Gaps and Sensitivity To Hmdumentioning

confidence: 99%

BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair

Lim

Zaman

Jasin

2023

Preprint

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Tumor suppressor BRCA2 functions in homology-directed repair (HDR), protection of stalled replication forks, and suppression of replicative gaps. The relative contributions of these pathways to genome integrity and chemotherapy response are under scrutiny. Here, we report that mouse and human cells require a RAD51 filament stabilization motif in BRCA2 for both fork protection and gap suppression, but not HDR. Loss of fork protection and gap suppression do not compromise genome instability or shorten tumor latency in mice or cause replication stress in human mammary cells. By contrast, HDR deficiency increases spontaneous and replication stress-induced chromosome aberrations and tumor predisposition. Unlike with HDR, fork protection and gap suppression defects are also observed in Brca2 heterozygous mouse cells, likely due to reduced RAD51 stabilization at stalled forks and gaps. Gaps arise from PRIMPOL activity, which is associated with sensitivity to 5-hydroxymethyl-2′-deoxyuridine due to the formation of abasic sites by SMUG1 glycosylase and is exacerbated by poly(ADP-ribose) polymerase inhibition. However, HDR deficiency ultimately modulates sensitivity to chemotherapeutics, including PARP inhibitors.

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Section: Primpol-dependent Ssdna Gaps and Sensitivity To Hmdumentioning

confidence: 99%

BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair

Lim

Zaman

Jasin

2023

Preprint

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“…To further verify the gene expression signatures before and after PARPi treatment, several gene expression levels were analyzed using qPCR with specific primers. FEN1 and SMUG1 are highly expressed and regarded as promising biomarkers in OC 14 , 15 . Therefore, changes in the expression of FEN1 and SMUG1 , as well as uracil-DNA glycosylases encoding gene UNG , after PARPi treatment were also evaluated to identify potential drug targets.…”

Section: Resultsmentioning

confidence: 99%

PARPi Decreased Primary Ovarian Cancer Organoid Growth Through Early Apoptosis and Base Excision Repair Pathway

Cao,

Li,

Zhao

et al. 2023

Cell Transplant

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Ovarian cancer (OC), particularly high-grade serous cancer (HGSC), is the leading cause of mortality among gynecological cancers owing to the treatment difficulty and high recurrence probability. As therapeutic drugs approved for OC, poly ADP-ribose polymerase inhibitors (PARPi) lead to synthetic lethality by inhibiting single-strand DNA repair, particularly in homologous recombination-deficient cancers. However, even PARPi have distinct efficacies and are prone to have drug resistance, the molecular mechanisms underlying the PARPi resistance in OC remain unclear. A patient-derived organoid platform was generated and treated with a PARPi to understand the factors associated with PARPi resistance. PARPi significantly inhibits organoid growth. After 72 h of treatment, both the size of organoids and the numbers of adherent cells decreased. Moreover, immunofluorescence results showed that the proportion of Ki67 positive cells significantly reduced. When the PARPi concentration reached 200 nM, the percentage of Ki67+/4′,6-diamidino-2-phenylindole (DAPI) cells decreased approximately 50%. PARPi treatment also affected the expression of genes involved in base excision repair and cell cycle. Functional assays revealed that PARPi inhibits cell growth by upregulating early apoptosis. The expression levels of several key genes were validated. In addition to previously reported genes, some promising genes FEN1 and POLA2, were also be founded. The results demonstrate the complex effects of PARPi treatment on changes in potential genes relevant to PARPi resistance, and provide perspectives for further research on the PARPi resistance mechanisms.

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“…Single-strand selective monofunctional glycosylase (SMUG1) works to remove 5-hmdU, uracil, 5-fluorouracil, and oxidized thymidine derivatives from DNA. The name is a misnomer, as SMUG1 can recognize and process substrates on both single-stranded and double-stranded DNA with almost equal activities [ 65 ]. The enzymatic activity of SMUG1 on nucleosomes has been previously studied by the Delaney group, and SMUG1 activity on lesions within nucleosomes decreases three- to nine-fold [ 17 ].…”

Section: Role Of Uv-ddb In 5-hydroxymethyl-2-deoxyuridine Repairmentioning

confidence: 99%

UV-DDB as a General Sensor of DNA Damage in Chromatin: Multifaceted Approaches to Assess Its Direct Role in Base Excision Repair

Raja

Houten

2023

IJMS

Self Cite

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Base excision repair (BER) is a cellular process that removes damaged bases arising from exogenous and endogenous sources including reactive oxygen species, alkylation agents, and ionizing radiation. BER is mediated by the actions of multiple proteins which work in a highly concerted manner to resolve DNA damage efficiently to prevent toxic repair intermediates. During the initiation of BER, the damaged base is removed by one of 11 mammalian DNA glycosylases, resulting in abasic sites. Many DNA glycosylases are product-inhibited by binding to the abasic site more avidly than the damaged base. Traditionally, apurinic/apyrimidinic endonuclease 1, APE1, was believed to help turn over the glycosylases to undergo multiple rounds of damaged base removal. However, in a series of papers from our laboratory, we have demonstrated that UV-damaged DNA binding protein (UV-DDB) stimulates the glycosylase activities of human 8-oxoguanine glycosylase (OGG1), MUTY DNA glycosylase (MUTYH), alkyladenine glycosylase/N-methylpurine DNA glycosylase (AAG/MPG), and single-strand selective monofunctional glycosylase (SMUG1), between three- and five-fold. Moreover, we have shown that UV-DDB can assist chromatin decompaction, facilitating access of OGG1 to 8-oxoguanine damage in telomeres. This review summarizes the biochemistry, single-molecule, and cell biology approaches that our group used to directly demonstrate the essential role of UV-DDB in BER.

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The Multiple Cellular Roles of SMUG1 in Genome Maintenance and Cancer

Cited by 13 publications

References 63 publications

BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair

BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair

PARPi Decreased Primary Ovarian Cancer Organoid Growth Through Early Apoptosis and Base Excision Repair Pathway

UV-DDB as a General Sensor of DNA Damage in Chromatin: Multifaceted Approaches to Assess Its Direct Role in Base Excision Repair

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