LAP2α preserves genome integrity through assisting RPA deposition on damaged chromatin

Bao, Kaiwen; Zhang, Qi; Liu, Shuai; Song, Nan; Guo, Qiushi; Liu, Ling; Tian, Shanshan; Hao, Jihui; Zhu, Yi Dan; Zhang, Kai; Ai, Ding; Yang, Jie; Yao, Zhi; Foisner, Roland; Shi, Lei

doi:10.1186/s13059-022-02638-6

Cited by 10 publications

(12 citation statements)

References 84 publications

(81 reference statements)

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“…These results indicate that SIRT7 and LAP2α knockout cause chromosome instability. LAP2α maintains genomic integrity by aiding RPA deposit on damaged chromatin 54 , and this result is consistent with the experimental results. Moreover, our results showed that SIRT7 regulates chromatin stabilization by directly binding to LAP2α protein in cancer cells.…”

Section: Discussionsupporting

confidence: 91%

SIRT7 Downregulation Promotes Breast Cancer Metastasis Via LAP2α-Induced Chromosomal Instability

Huo¹,

Chen²,

Liu³

et al. 2023

Int. J. Biol. Sci.

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Chromosomal instability (CIN) plays an important role in the initiation and progression of carcinomas. However, the regulatory mechanism of metastasis mediated by CIN in breast cancer is not fully understood. Here, we aimed to demonstrate that the deregulation of SIRT7 and lamina-associated polypeptide 2α (LAP2α) critically contributes to CIN-induced metastasis in breast cancer. Expression of SIRT7 and chromosome stability-related genes was examined using western blotting, quantitative real-time PCR, immunohistochemistry, and immunofluorescence; functional significance of SIRT7 was examined using in vitro and in vivo models; and interaction between SIRT7 and LAP2α was assessed by co-inmunoprecipitation (Co-IP) assays. Doxorubicin (DOX) inhibited SIRT7 expression and enhanced CIN in breast cancer cells; SIRT7 deficiency led to CIN in breast cancer cells. Co-IP approach and immunohistochemistry demonstrated that SIRT7 interacted directly and positively with LAP2α and SIRT7 knockdown led to increased ubiquitination-dependent degradation of LAP2α and reduced protein levels of LAP2α, whereas LAP2α knockdown did not affect SIRT7 expression. In vitro and in vivo evidence revealed that SIRT7 promotes breast cancer metastasis through the SIRT7/LAP2α axis. In summary, SIRT7 interacts with LAP2α to regulate CIN and metastasis in breast cancer, and inhibition of SIRT7/LAP2α axis represents a potential therapeutic strategy for preventing breast cancer metastasis.

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Section: Discussionsupporting

confidence: 91%

SIRT7 Downregulation Promotes Breast Cancer Metastasis Via LAP2α-Induced Chromosomal Instability

Huo¹,

Chen²,

Liu³

et al. 2023

Int. J. Biol. Sci.

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“…Moreover, Ir-CA could overcome the cisplatin resistance of A549R cells (Table ). GSEA revealed that the gene set of drug metabolism-cytochrome associated with platinum drug resistance has been dramatically regulated as the down-regulation of cisplatin detoxification GSTP1 (glutathione S-transferase P1) and GSTM4 (glutathione S-transferase M4) (Figure C,G). , DNA repair systems were also deactivated after the Ir-CA treatment, as the expressions of genes PCNA, RPA1, RPA2, RPA3, and PARP1 were down-regulated (Figure C). , This would facilitate the understanding of the mechanism for the capacity to overcome cisplatin resistance of Ir-CA .…”

Section: Resultsmentioning

confidence: 95%

“…45,46 DNA repair systems were also deactivated after the Ir-CA treatment, as the expressions of genes PCNA, RPA1, RPA2, RPA3, and PARP1 were down-regulated (Figure 3C). 47,48 This would facilitate the understanding of the mechanism for the capacity to overcome cisplatin resistance of Ir-CA.…”

Section: Occurrence Of Mitophagy and Cell Cycle Arrestmentioning

confidence: 99%

Consolidating Organometallic Complex Ir-CA Empowers Mitochondria-Directed Chemotherapy against Resistant Cancer via Stemness and Metastasis Inhibition

Yang,

Wang,

Deng

et al. 2024

Inorg. Chem.

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Cancer treatment has faced severe obstacles due to the smart biological system of cancer cells. Herein, we report a three-in-one agent Ir-CA via attenuation of cancer cell stemness with the down-regulated biomarker CD133 expression from the mitochondriadirected chemotherapy. Over 80% of Ir-CA could accumulate in mitochondria, result in severe mitochondrial dysfunctions, and subsequently initiate mitophagy and cell cycle arrest to kill cisplatin-resistant A549R cells. In vitro and in vivo antimetastatic experiments demonstrated that Ir-CA can effectively inhibit metastasis with down-regulated MMP-2/ MMP-9. RNA seq analysis and Western blotting indicated that Ir-CA also suppresses the GSTP1 expression to decrease the intracellular Pt-GS adducts, resulting in the detoxification and resensitization to cisplatin of A549R cells. In vivo evaluation indicated that Ir-CA restrains the tumor growth and has minimal side effects and superior biocompatibility. This work not only provides the first three-in-one agent to attenuate cancer cell stemness and simultaneously realize anticancer, antimetastasis, and conquer metallodrug resistance but also demonstrates the effectiveness of the mitochondria-directed strategy in cancer treatment.

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“…While a recent study reported that LAP2α could associate with Replication Protein A (RPA) and facilitate its deposition to damaged chromatin during homologous recombination 35 . However, our ndings reveal a distinctive occurrence at telomere, that the disruption of LAP2α increases the recruitment of RPA to telomeric DNA.…”

Section: Discussionmentioning

confidence: 99%

LAP2α Orchestrates Alternative Lengthening of Telomeres Suppression through Telomeric Heterochromatin Regulation with HDAC1: Unveiling a Potential Therapeutic Target

Wang

2024

Preprint

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In response to the challenge of telomere attrition during DNA replication, cancer cells predominantly employ telomerase or, in 10%-15% of cases, the alternative lengthening of telomeres (ALT). The intricate details of ALT, however, remain elusive. In this study, we unveil that the knockdown of lamina-associated polypeptide 2 alpha (LAP2α) in ALT cells results in telomere dysfunction, triggering a notable increase in ALT-associated hallmarks, including high frequencies of PML bodies (APBs), C-rich extrachromosomal circles (C-circles), and telomere sister chromatid exchange (T-SCE). Furthermore, LAP2α emerges as a crucial player in the process of break-induced telomere replication for telomerase-positive cells following telomeric double-strand breaks. Mechanistically, our investigation underscores LAP2α's role in hindering the recruitment of homologous recombination factors (e.g., RAD52 and RPA2) to telomeres. This occurs through the regulation of the heterochromatic state of telomeres, thereby increasing telomeric accessibility. Consistent with our findings, LAP2α expression is markedly diminished in ALT-positive Osteosarcoma. The use of methotrexate (MTX), which restores the lost heterochromatin state induced by LAP2α depletion, effectively reverses ALT characteristics. This is highlighted by a significant inhibition of tumor proliferation, specifically in ALT-positive patient-derived xenograft (PDX) mouse models. These results underscore the critical role of LAP2α in regulating ALT activity, offering significant insights into the interplay between lamina-associated proteins and telomeres for maintaining telomere length. Of paramount significance, our findings contribute to the identification of a more appropriate target population for the osteosarcoma therapeutic drug, MTX.

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LAP2α preserves genome integrity through assisting RPA deposition on damaged chromatin

Cited by 10 publications

References 84 publications

SIRT7 Downregulation Promotes Breast Cancer Metastasis Via LAP2α-Induced Chromosomal Instability

SIRT7 Downregulation Promotes Breast Cancer Metastasis Via LAP2α-Induced Chromosomal Instability

Consolidating Organometallic Complex Ir-CA Empowers Mitochondria-Directed Chemotherapy against Resistant Cancer via Stemness and Metastasis Inhibition

LAP2α Orchestrates Alternative Lengthening of Telomeres Suppression through Telomeric Heterochromatin Regulation with HDAC1: Unveiling a Potential Therapeutic Target

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