Aberrantly expressed HORMAD1 disrupts nuclear localization of MCM8–MCM9 complex and compromises DNA mismatch repair in cancer cells

Liu, Kang; Wang, Yifan; Zhu, Quanfeng; Chen, Jiyuan; Tang, Zhenghui; Shen, Yuanming; Cheng, Xiaodong; Lu, Lin-Yu; Liu, Yidan

doi:10.1038/s41419-020-2736-1

Cited by 32 publications

(39 citation statements)

References 37 publications

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“…Overexpression of HORMAD1, a meiosis-specific protein aberrantly expressed in various cancers, was also shown to inhibit MMR through the cytosolic sequestration of the MCM9 helicase (80) that normally stimulates the chromatin recruitment of MLH1 and contributes to MMR in vivo (66,80). Future research will help determine in which circumstances inhibiting this crucial genome maintenance pathway is beneficial.…”

Section: )mentioning

confidence: 99%

SLX4 dampens MutSα-dependent mismatch repair

Guervilly

Blin

Laureti

et al. 2021

Preprint

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The tumour suppressor SLX4 plays multiple roles in the maintenance of genome stability, acting as a scaffold for structure-specific endonucleases and other DNA repair proteins. It directly interacts with the mismatch repair (MMR) protein MSH2 but the significance of this interaction remained unknown until recent findings showing that MutSβ (MSH2-MSH3) stimulates in vitro the SLX4-dependent Holliday junction resolvase activity. Here, we characterize the mode of interaction between SLX4 and MSH2, which relies on an MSH2-interacting peptide (SHIP box) that drives interaction of SLX4 with both MutSβ and MutSα (MSH2-MSH6). While we show that this MSH2 binding domain is dispensable for the well-established role of SLX4 in interstrand crosslink repair, we find that it mediates inhibition of MutSα-dependent MMR by SLX4, unravelling an unanticipated function of SLX4.

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Section: )mentioning

confidence: 99%

SLX4 dampens MutSα-dependent mismatch repair

Guervilly

Blin

Laureti

et al. 2021

Preprint

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“…HORMAD1 is a specific germ cell protein known to be reactivated in certain cancer types ( 11 ). HORMAD1 belongs to a family of proteins [meiosis-specific protein HOP1, mitotic arrest deficient 2 like 2, mitotic arrest deficient 2 like 1 (Mad2)] characterized by a HORMA domain that is present in several DNA repair pathways ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

“…As a consequence, HORMAD1-expressing cancer cells exhibited reduced mutL homolog 1 chromatin binding and DNA mismatch repair defects. Therefore, HORMAD1 expression was associated with an increased mutation load and genomic instability in several types of cancer ( 11 ). However, whether this is related to the increased Doc sensitivity caused by HORMAD1 knockdown still requires further study.…”

Section: Discussionmentioning

confidence: 99%

“…Cancer testis antigens (CTAs) are genes named after their expression patterns, since they are usually expressed only in the testes, where they play important roles in homologous chromosome recombination during meiosis, but also exhibit an abnormally high expression in a variety of malignant tumors ( 11 ). HORMA domain-containing protein 1 (HORMAD1; also referred to as CT46) is a CTA normally expressed in the testes, which has also been revealed to be expressed in female gametes and to have important physiological functions ( 12 ), with abnormally high levels in TNBC ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

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HORMAD1 promotes docetaxel resistance in triple negative breast cancer by enhancing DNA damage tolerance

et al. 2021

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HORMA domain-containing protein 1 (HORMAD1), is normally expressed only in the germline, but is frequently re-activated in human triple-negative breast cancer (TNBC); however, its function in TNBC is largely unknown. In the present study, the expression and biological significance of HORMAD1 in human TNBC was evaluated. Bioinformatics analysis and reverse transcription-quantitative PCR were used to evaluate HORMAD1 expression in datasets and cell lines. HORMAD1 protein expression was detected in TNBC samples using immunohistochemical assays, and the effect of HORMAD1 on cell proliferation was determined using Cell Counting Kit-8, plate colony formation and standard growth curve assays. Cell cycle, reactive oxygen species (ROS) and apoptosis analyses were conducted using flow cytometry. The activity of caspases was measured using caspase activity assay kit. The levels of key apoptosis regulators and autophagy markers were detected by western blot analysis. TNBC cell survival and apoptosis were not influenced by small interfering RNA targeting HORMAD1 alone; however, HORMAD1 knockdown enhanced autophagy and docetaxel (Doc)-induced apoptosis, compared with the control group. Furthermore, higher ROS levels and caspase-3, -8 and -9 activity were detected in MDA-MB-436 TNBC cells with HORMAD1 knockdown upon exposure to Doc. The levels of the induced DNA damage marker γH2AX were also higher, while those of the DNA repair protein RAD51 were lower in TNBC cells with HORMAD1 knockdown compared with the controls. Furthermore, the expression of the autophagy marker P62 was enhanced in MDA-MB-231 cells in response to HORMAD1 overexpression. Notably, Doc-induced apoptosis was similarly increased by both HORMAD1 overexpression and treatment with the autophagy inhibitor, 3-methyladenine (3MA); however, the Doc-induced increase in autophagy was not inhibited by 3MA. The present data indicated that HORMAD1 was involved in autophagy and that the inhibition of autophagy can partially enhance the induction of apoptosis by Doc. The role of HORMAD1 in the DNA damage tolerance of tumor cells may be the main reason for Doc resistance; hence, HORMAD1 could be an important therapeutic target in TNBC.

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“…Recent new research shows that HORMAD1 can enhance the tolerance of DDR and promote the resistance of triple-negative breast cancer to chemotherapeutic drugs [50]. HORMAD1 is a specific germ cell protein that plays an important role in homologous chromosome recombination, and is reactivated in breast cancer, showing abnormally high expression [51]. Studies have shown that under the conditions of oxidative stress induced by related chemotherapy drugs, HORMAD1 may regulate the expression of enzymes in breast cancer cells to enhance the ability to resist apoptosis, which may be the main factor in inducing chemotherapy resistance.…”

Section: Dna Damage Repairmentioning

confidence: 99%

New Advances in the Research of Resistance to Neoadjuvant Chemotherapy in Breast Cancer

Peng

Tang

et al. 2021

IJMS

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Breast cancer has an extremely high incidence in women, and its morbidity and mortality rank first among female tumors. With the increasing development of medicine today, the clinical application of neoadjuvant chemotherapy has brought new hope to the treatment of breast cancer. Although the efficacy of neoadjuvant chemotherapy has been confirmed, drug resistance is one of the main reasons for its treatment failure, contributing to the difficulty in the treatment of breast cancer. This article focuses on multiple mechanisms of action and expounds a series of recent research advances that mediate drug resistance in breast cancer cells. Drug metabolizing enzymes can mediate a catalytic reaction to inactivate chemotherapeutic drugs and develop drug resistance. The drug efflux system can reduce the drug concentration in breast cancer cells. The combination of glutathione detoxification system and platinum drugs can cause breast cancer cells to be insensitive to drugs. Changes in drug targets have led to poorer efficacy of HER2 receptor inhibitors. Moreover, autophagy, epithelial–mesenchymal transition, and tumor microenvironment can all contribute to the development of resistance in breast cancer cells. Based on the relevant research on the existing drug resistance mechanism, the current treatment plan for reversing the resistance of breast cancer to neoadjuvant chemotherapy is explored, and the potential drug targets are analyzed, aiming to provide a new idea and strategy to reverse the resistance of neoadjuvant chemotherapy drugs in breast cancer.

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Aberrantly expressed HORMAD1 disrupts nuclear localization of MCM8–MCM9 complex and compromises DNA mismatch repair in cancer cells

Cited by 32 publications

References 37 publications

SLX4 dampens MutSα-dependent mismatch repair

SLX4 dampens MutSα-dependent mismatch repair

HORMAD1 promotes docetaxel resistance in triple negative breast cancer by enhancing DNA damage tolerance

New Advances in the Research of Resistance to Neoadjuvant Chemotherapy in Breast Cancer

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