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HMGA1 accumulates at damage sites, interacts with PARP1, and is PARylated at E47/E50 within the AT-hook 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does HMGA1 PARylation do in response to DNA damage?","Question",{"text":63,"@type":64},"HMGA1 undergoes PARylation at E47 and E50 after DNA damage, where it interacts with PARP1 at DNA damage sites and supports downstream DNA repair activities.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How does this affect sensitivity to olaparib in ESCC?",{"text":68,"@type":64},"PARylation of HMGA1 desensitizes ESCC cells to the PARP1 inhibitor olaparib, reducing therapeutic sensitivity.",{"name":70,"@type":61,"acceptedAnswer":71},"What evidence supports the involvement of HMGA1 in DNA repair and tumor outcomes?",{"text":72,"@type":64},"The study links HMGA1 interference with increased tumor sensitivity to olaparib in multiple in vivo models and shows that HMGA1 is highly expressed in ESCC tissues and correlates with PARP1 levels and poor 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olaparib  \nXin-Yuan Lei   Kai-Yue He  Qiu-Tong Li  Lei Zhang  Dan-Hui Wu  Jing-Yu Yang  Jin-Rong Guo  Meng-Jie Liu  Zi-Long Zhao  Jun-Qi Li  Huai Liu  Yuan Zhao  Yu-Jia Li  Qian-Hui Sun  Chen-Guang Wu   \nYun-Fan Wang  Geng-Sheng Cao  Gang Wang  Yong-Ping Jian  Zhi-Xiang Xu  \nSchool of Life Sciences, Henan University, Kaifeng, China  \nCorrespondence  \nZhi-Xiang Xu and Yong-Ping Jian, School of Life Sciences, Henan University, Kaifeng, Henan Province 475000, China. Email: zhixiangxu08@gmail.com and [yongpingjian123@163.com](yongpingjian123@163.com)  \nGraphical Abstract  \nClin. Transl. Med. 2024;14:e70111 .  \n[https://doi.org/10.1002/ctm2.70111](https://doi.org/10.1002/ctm2.70111)  \n[wileyonlinelibrary.com/journal/ctm2](wileyonlinelibrary.com/journal/ctm2)  \nDOI: 10.1002/ctm2.70111  \nRESEARCH ARTICLE  \nPARylation ofHMGA1 desensitizes esophageal squamous cell carcinoma to olaparib  \nXin-Yuan Lei   Kai-Yue He  Qiu-Tong Li  Lei Zhang  Dan-Hui Wu  Jing-Yu Yang  Jin-Rong Guo  Meng-Jie Liu  Zi-Long Zhao  Jun-Qi Li  Huai Liu  Yuan Zhao  Yu-Jia Li  Qian-Hui Sun  Chen-Guang Wu   \nYun-Fan Wang  Geng-Sheng Cao  Gang Wang  Yong-Ping Jian  Zhi-Xiang Xu  \nSchool of Life Sciences, Henan University, Kaifeng, China  \nCorrespondence  \nZhi-Xiang Xu and Yong-Ping Jian, School of Life Sciences, Henan University, Kaifeng, Henan Province 475000, China. Email: [zhixiangxu08@gmail.com](zhixiangxu08@gmail.com) and [yongpingjian123@163.com](yongpingjian123@163.com)  \nFunding information  \nNational Key Research and Development Program of China, Grant/Award Number: 2023YFE0109800; National Natural Science Foundation of China,  \nGrant/Award Numbers: 82020108024, 82200596, 82400658; China Postdoctoral Science Foundation, Grant/Award Number: 2022M721014  \nAbstract  \nAs a chromatin remodelling factor, high mobility group A1 (HMGA1) plays various roles in both physiological and pathological conditions. However, its role in DNA damage response and DNA damage-based chemotherapy remains largely unexplored. In this study, we report the poly ADP-ribosylation (PARylation) of HMGA1 during DNA damage, leading to desensitization of esophageal squamous cell carcinoma (ESCC) cells to the poly(ADP-ribose) polymerase 1 (PARP1) inhibitor, olaparib. We found that HMGA1 accumulates at sites of DNA damage, where it interacts with PARP1 and undergoes PARylation at residuesE47 and E50 in its conserved AT-hook domain. This modification enhances the accumulation of Ku70/Ku80 at the site of DNA damage and activates the DNA-dependent protein kinase catalytic subunit, facilitating nonhomologous end-joining repair. In both subcutaneous tumour models and genetically engineered mouse models of in situ esophageal cancer, HMGA1 interference increased tumour sensitivity toolaparib. Moreover, HMGA1 was highly expressed in ESCC tissues and positively correlated with PARP1 levels as well as poor prognosis in ESCC patients. Taken together, these findings reveal a mechanistic link between HMGA1 and PARP1 in regulating cell responses to DNA damage and suggest that targeting HMGA1 could be a promising strategy to increase cancer cell sensitivity to olaparib.  \nKEYWORDS  \nchemotherapy sensitivity, DNA damage, ESCC, HMGA1, Olaparib, PARP1, PARylation  \n1  INTRODUCTION  \nEsophageal cancer (EC) is one of the most common malignant tumours in the world, with high morbidity and mortality, which seriously affects public health.1,2  \nThere are two primary histological types of EC: ESCC and esophageal adenocarcinoma (EAC) .3,4 ESCC is the most common form and accounts for the highest incidence and mortality rates, particularly in Eastern countries. Overall, EC ranks seventh in incidence and sixth in mortality.5  \nThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is ","cbCaie27RDVlqiKM","https://ap.wps.com/l/cbCaie27RDVlqiKM","pdf",21047564,23,"English","# Introduction\n## DNA damage response and DNA repair pathways\n## Roles of PARP1 and PARylation\n# Abstract","[{\"question\":\"What does HMGA1 PARylation do in response to DNA damage?\",\"answer\":\"HMGA1 undergoes PARylation at E47 and E50 after DNA damage, where it interacts with PARP1 at DNA damage sites and supports downstream DNA repair activities.\"},{\"question\":\"How does this affect sensitivity to olaparib in ESCC?\",\"answer\":\"PARylation of HMGA1 desensitizes ESCC cells to the PARP1 inhibitor olaparib, reducing therapeutic sensitivity.\"},{\"question\":\"What evidence supports the involvement of HMGA1 in DNA repair and tumor outcomes?\",\"answer\":\"The study links HMGA1 interference with increased tumor sensitivity to olaparib in multiple in vivo models and shows that HMGA1 is highly expressed in ESCC tissues and correlates with PARP1 levels and poor prognosis.\"}]","PARylation of HMGA1 desensitizes esophageal squamous cell carcinoma to olaparib | PDF",1790024331,58]