PWWP2B promotes DNA end resection and homologous recombination

Ju, Min Kyung; Lee, Joo Rak; Choi, Yeonsong; Park, Seon Young; Sul, Hee Jung; Chung, Hee Jin; An, Soyeong; Lee, Semin; Jung, Eun‐Young; Kim, Bohyun; Choi, Bo Youn; Kim, Bum Joon; Kim, Hyeong Su; Lim, Hyun; Kang, Ho Suk; Soh, Jae Seung; Myung, Kyungjae; Kim, Kab Choong; Cho, Ji Woong; Seo, Jinwon; Kim, Tae Moon; Lee, Ja Yil; Kim, Yonghwan; Kim, Hongtae; Zang, Dae Young

doi:10.15252/embr.202153492

Cited by 4 publications

(2 citation statements)

References 53 publications

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“…Moreover, a study investigating other DDR-associated genes utilized whole exome sequencing (WES) and bioinformatics tools, revealing that PWWP (Pro-Trp-Trp-Pro) domain containing 2B (PWWP2B) is among the frequently mutated genes in tissues of Korean patients with gastric adenocarcinoma [104]. PWWP2B plays a crucial role in DDR and homologous recombination-mediated DSB repair through its interaction with ubiquitin-like with PHD and RING finger domains1 (UHRF1).…”

Section: Homologous Recombination Deficiency In Gcmentioning

confidence: 99%

Advancements and Obstacles of PARP Inhibitors in Gastric Cancer

Chen,

Hu,

Zhuang

et al. 2023

Cancers

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Gastric cancer (GC) is a common and aggressive cancer of the digestive system, exhibiting high aggressiveness and significant heterogeneity. Despite advancements in improving survival rates over the past few decades, GC continues to carry a worrisome prognosis and notable mortality. As a result, there is an urgent need for novel therapeutic approaches to address GC. Recent targeted sequencing studies have revealed frequent mutations in DNA damage repair (DDR) pathway genes in many GC patients. These mutations lead to an increased reliance on poly (adenosine diphosphate-ribose) polymerase (PARP) for DNA repair, making PARP inhibitors (PARPi) a promising treatment option for GC. This article presents a comprehensive overview of the rationale and development of PARPi, highlighting its progress and challenges in both preclinical and clinical research for treating GC.

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Section: Homologous Recombination Deficiency In Gcmentioning

confidence: 99%

Advancements and Obstacles of PARP Inhibitors in Gastric Cancer

Chen,

Hu,

Zhuang

et al. 2023

Cancers

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“…DNA end resection has a critical role in the initiation of double strand breaks ends for efficient homologous recombination repair, regulating DNA damage repair and cell radiosensitivity [16][17][18][19]. Previous studies suggested that DNA end resection factors regulated the generation of ssDNA fragments and initiation of innate immune responses [20,21].…”

Section: Samhd1 Silencing Caused Cytosolic Ssdna Accumulation In Luadmentioning

confidence: 99%

SAMHD1 silencing cooperates with radiotherapy to enhance anti-tumor immunity through IFI16-STING pathway in lung adenocarcinoma

Gao

Jiang

et al. 2022

J Transl Med

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Background Sterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) is a DNA end resection factor, which is involved in DNA damage repair and innate immunity. However, the role of SAMHD1 in anti-tumor immunity is still unknown. This study investigated the effects of SAMHD1 on stimulator of interferon genes (STING)-type I interferon (IFN) pathway and radiation-induced immune responses. Methods The roles of SAMHD1 in the activation of cytosolic DNA sensing STING pathway in lung adenocarcinoma (LUAD) cells were investigated with flow cytometry, immunofluorescence, immunoblotting and qPCR. The combined effects of SAMHD1 silencing and radiation on tumor cell growth and STING pathway activation were also evaluated with colony formation and CCK8 assay. The Lewis lung cancer mouse model was used to evaluate the combined efficiency of SAMHD1 silencing and radiotherapy in vivo. Macrophage M1 polarization and cytotoxic T cell infiltration were evaluated with flow cytometry. Results The single-stranded DNA (ssDNA) accumulated in the cytosol of SAMHD1-deficient lung adenocarcinoma (LUAD) cells, accompanied by upregulated DNA sensor IFN-γ-inducible protein 16 (IFI16) and activated STING pathway. The translocation of IFI16 from nucleus to cytosol was detected in SAMHD1-deficient cells. IFI16 and STING were acquired in the activation of STING-IFN-I pathway in SAMHD1-deficient cells. SAMHD1 silencing in LUAD cells promoted macrophage M1 polarization in vitro. SAMHD1 silencing synergized with radiation to activate ssDNA-STING-IFN-I pathway, inhibit proliferation, promote apoptosis and regulate cell cycle. SAMHD1 silencing cooperated with radiotherapy to inhibit tumor growth and increase CD86+MHC-IIhigh M1 proportion and CD8+ T cell infiltration in vivo. Conclusions SAMHD1 deficiency induced IFN-I production through cytosolic IFI16-STING pathway in LUAD cells. Moreover, SAMHD1 downregulation and radiation cooperated to inhibit tumor growth and enhance anti-tumor immune responses through macrophage M1 polarization and CD8+ T cell infiltration. Combination of SAMHD1 inhibition and radiotherapy may be a potentially therapeutic strategy for LUAD patients.

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