Defining a fundamental role for histone methylation in preventing DNA damage-induced replication catastrophe
确定组蛋白甲基化在预防 DNA 损伤诱导的复制灾难中的基本作用
基本信息
- 批准号:MR/M009882/1
- 负责人:
- 金额:$ 44.31万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2015
- 资助国家:英国
- 起止时间:2015 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Duplication of the cell's genome is essential for the continuation of life, and this must occur in an efficient and well-timed manner to ensure that each daughter cell gets the correct amount of genetic material. The presence of damage within the cell's DNA can slow or stall the DNA replication machinery, preventing the timely completion of genome duplication. This can result in either cell death, if the unrepaired damage is too great, or transfer of the damage into the daughter cells when the cell divides, which can cause mutations. The accumulation of DNA damage and mutations over time is a fundamental part of the process in which normal healthy cells undergo transformation into tumour cells. It is therefore clear that problems with repairing damage that occurs during DNA replication are a significant cause of human disease and cancer.To prevent genetic damage from persisting, cells have evolved a highly complex network of cellular pathways that recognise and repair DNA damage. One of the most important DNA repair pathways that functions during DNA replication is the Fanconi Anaemia (FA) pathway. The FA pathway is named after the rare human disease, Fanconi Anaemia, which is associated with severe clinical symptoms such as growth retardation, limb malformation, brain abnormalities, progressive bone marrow failure leading to anaemia and an increased predisposition for developing cancer. To date, it has been found that mutations in any one of 16 different genes, all working within the same pathway, can give rise to FA. The study of rare human syndromes, such as FA, has dramatically increased our knowledge about how DNA repair pathways protect the cell from genetic damage, and the consequences when this process fails. However, despite our progress, we still do not fully understand some fundamental aspects of how these pathways function or indeed whether additional factors exist that are yet to be discovered. Indeed, patients suffering from an FA-like disorder have been identified in whom the disease-causing mutation has yet to be discovered.In this respect, we have identified a new protein (PFAP; Putative Fanconi Anaemia Protein) that functions to help repair DNA damage that arises during DNA replication. Interestingly, the defects caused by loss of PFAP are strikingly similar to those observed in cells from FA patients, suggesting that PFAP functions within the FA pathway, and may even be mutated in patients exhibiting FA-like symptoms. In addition, we have discovered that PFAP binds to an enzyme called HMT-1 (Histone Methyltransferase 1), whose primary role is to modify the structure of proteins surrounding DNA (called chromatin) through a process called methylation. Strikingly, loss of HMT-1 gives rise to the same problems as we observed in cells lacking PFAP, indicative of a biochemical link between 'chromatin methylation' and the FA repair pathway.Whilst we know that chromatin methylation can alter the way cells respond to certain types of DNA damage, it is unknown how it affects the FA pathway. Therefore, this application aims to investigate this, using three different approaches. Firstly, we aim to establish where PFAP functions within the FA pathway and ascertain whether PFAP is mutated in cells derived from patients exhibiting an FA-like disorder. Secondly, we aim to understand how PFAP controls DNA replication in the presence of DNA damage. Lastly, we aim to determine if chromatin methylation carried out by PFAP/HMT-1 contributes to how replication-associated DNA damage is repaired.The proposed research on this fundamental and highly conserved aspect of the cellular response to DNA damage has the potential to make a significant long-term impact on improving human health and wellbeing. In addition to furthering our understanding of how normal cells transform into tumour cells, it could also aid the diagnosis of FA-like disorders and/or facilitate the development of new chemotherapeutic drugs to treat cancer.
细胞基因组的复制对于生命的延续是必不可少的,这必须以有效和及时的方式进行,以确保每个子细胞获得正确数量的遗传物质。细胞DNA内部的损伤会减慢或停止DNA复制机制,阻止基因组复制的及时完成。如果未修复的损伤太大,这可能导致细胞死亡,或者在细胞分裂时将损伤转移到子细胞中,这可能导致突变。随着时间的推移,DNA损伤和突变的积累是正常健康细胞转化为肿瘤细胞过程的基本组成部分。因此,很明显,DNA复制过程中出现的修复损伤问题是人类疾病和癌症的一个重要原因。为了防止遗传损伤持续存在,细胞已经进化出了一个高度复杂的细胞通路网络来识别和修复DNA损伤。在DNA复制过程中起作用的最重要的DNA修复途径之一是范可尼贫血(Fanconi anemia, FA)途径。FA通路是以一种罕见的人类疾病——范可尼贫血(Fanconi anemia)命名的,这种疾病与严重的临床症状有关,如生长迟缓、肢体畸形、大脑异常、进行性骨髓衰竭导致贫血,以及患癌症的易感性增加。迄今为止,已经发现16种不同基因中的任何一种的突变都可以导致FA,这些基因都在同一途径中起作用。对罕见的人类综合症的研究,如FA,极大地增加了我们对DNA修复途径如何保护细胞免受遗传损伤的认识,以及当这一过程失败时的后果。然而,尽管我们取得了进展,我们仍然不完全了解这些途径如何发挥作用的一些基本方面,或者是否存在尚未发现的其他因素。事实上,患有fa样疾病的患者已经被确定,但其致病突变尚未被发现。在这方面,我们已经鉴定出一种新的蛋白(PFAP;推定范可尼贫血蛋白),它的功能是帮助修复DNA复制过程中产生的DNA损伤。有趣的是,PFAP缺失引起的缺陷与FA患者细胞中观察到的缺陷惊人地相似,这表明PFAP在FA通路中起作用,甚至可能在出现FA样症状的患者中发生突变。此外,我们还发现PFAP与一种名为HMT-1(组蛋白甲基转移酶1)的酶结合,该酶的主要作用是通过甲基化过程修饰DNA周围蛋白质(称为染色质)的结构。引人注目的是,HMT-1的缺失引起了与我们在缺乏PFAP的细胞中观察到的相同的问题,这表明“染色质甲基化”与FA修复途径之间存在生化联系。虽然我们知道染色质甲基化可以改变细胞对某些类型DNA损伤的反应方式,但尚不清楚它如何影响FA途径。因此,本应用程序旨在使用三种不同的方法对此进行调查。首先,我们的目标是确定PFAP在FA通路中的作用,并确定PFAP是否在表现FA样疾病的患者的细胞中发生突变。其次,我们的目标是了解PFAP如何在DNA损伤的情况下控制DNA复制。最后,我们的目标是确定PFAP/HMT-1进行的染色质甲基化是否有助于如何修复复制相关的DNA损伤。关于细胞对DNA损伤反应的这一基本和高度保守的方面的拟议研究有可能对改善人类健康和福祉产生重大的长期影响。除了进一步加深我们对正常细胞如何转化为肿瘤细胞的理解外,它还可以帮助诊断fa样疾病和/或促进开发新的化疗药物来治疗癌症。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
PRMT5-Dependent Methylation of the TIP60 Coactivator RUVBL1 Is a Key Regulator of Homologous Recombination.
- DOI:10.1016/j.molcel.2017.01.019
- 发表时间:2017-03-02
- 期刊:
- 影响因子:16
- 作者:Clarke TL;Sanchez-Bailon MP;Chiang K;Reynolds JJ;Herrero-Ruiz J;Bandeiras TM;Matias PM;Maslen SL;Skehel JM;Stewart GS;Davies CC
- 通讯作者:Davies CC
H3K4 methylation by SETD1A/BOD1L facilitates RIF1-dependent NHEJ.
- DOI:10.1016/j.molcel.2022.03.030
- 发表时间:2022-05-19
- 期刊:
- 影响因子:16
- 作者:Bayley, Rachel;Borel, Valerie;Moss, Rhiannon J.;Sweatman, Ellie;Ruis, Philip;Ormrod, Alice;Goula, Amalia;Mottram, Rachel M. A.;Stanage, Tyler;Hewitt, Graeme;Saponaro, Marco;Stewart, Grant S.;Boulton, Simon J.;Higgs, Martin R.
- 通讯作者:Higgs, Martin R.
Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism.
- DOI:10.1038/ng.3790
- 发表时间:2017-04
- 期刊:
- 影响因子:30.8
- 作者:Reynolds JJ;Bicknell LS;Carroll P;Higgs MR;Shaheen R;Murray JE;Papadopoulos DK;Leitch A;Murina O;Tarnauskaitė Ž;Wessel SR;Zlatanou A;Vernet A;von Kriegsheim A;Mottram RM;Logan CV;Bye H;Li Y;Brean A;Maddirevula S;Challis RC;Skouloudaki K;Almoisheer A;Alsaif HS;Amar A;Prescott NJ;Bober MB;Duker A;Faqeih E;Seidahmed MZ;Al Tala S;Alswaid A;Ahmed S;Al-Aama JY;Altmüller J;Al Balwi M;Brady AF;Chessa L;Cox H;Fischetto R;Heller R;Henderson BD;Hobson E;Nürnberg P;Percin EF;Peron A;Spaccini L;Quigley AJ;Thakur S;Wise CA;Yoon G;Alnemer M;Tomancak P;Yigit G;Taylor AM;Reijns MA;Simpson MA;Cortez D;Alkuraya FS;Mathew CG;Jackson AP;Stewart GS
- 通讯作者:Stewart GS
Histone Methylation by SETD1A Protects Nascent DNA through the Nucleosome Chaperone Activity of FANCD2.
- DOI:10.1016/j.molcel.2018.05.018
- 发表时间:2018-07-05
- 期刊:
- 影响因子:16
- 作者:Higgs MR;Sato K;Reynolds JJ;Begum S;Bayley R;Goula A;Vernet A;Paquin KL;Skalnik DG;Kobayashi W;Takata M;Howlett NG;Kurumizaka H;Kimura H;Stewart GS
- 通讯作者:Stewart GS
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Grant Stewart其他文献
Survival trends of renal cell cancer patients treated with neoadjuvant tyrosine kinase inhibitors before cytoreductive nephrectomies
- DOI:
10.1016/j.ejso.2017.10.116 - 发表时间:
2017-11-01 - 期刊:
- 影响因子:
- 作者:
Manavi Sachdeva;Sarah Welsh;Grant Stewart;Kate Fife - 通讯作者:
Kate Fife
225 Durvalumab (D) as consolidation therapy in limited-stage SCLC (LS-SCLC): Outcomes by prior concurrent chemoradiotherapy (cCRT) regimen and prophylactic cranial irradiation (PCI) use in the ADRIATIC trial
225 度伐利尤单抗(D)作为局限期小细胞肺癌(LS-SCLC)的巩固治疗:ADRIATIC 试验中根据既往同步放化疗(cCRT)方案和预防性颅脑照射(PCI)使用情况的结果
- DOI:
10.1016/j.lungcan.2025.108334 - 发表时间:
2025-02-01 - 期刊:
- 影响因子:4.400
- 作者:
Grant Stewart;Suresh Senan;D.R. Spigel;B.C. Cho;K. Laktionov;Y. Zenke;K.H. Lee;Q Wang;A.F. Navarro Mendivil;E.L. Buchmeier;S. Sezgin Goksu;A. Badzio;A. Shi;D.B. Daniel;M. Zemanova;P. Iyengar;L.G. Paz-Ares;L. Szadkowski;P. Chugh;W.C.V. Lai;Y. Cheng - 通讯作者:
Y. Cheng
Investigative Report on Electrical Commissioning in HPC Data Centers
HPC数据中心电气调试调查报告
- DOI:
10.1109/cluster49012.2020.00074 - 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
Joe Prisco;Grant Stewart;Herbert Huber;Randy K. Rannow;Jason Hick;Dave Martinez;Brandon Hong;Aditya M. Deshpande - 通讯作者:
Aditya M. Deshpande
Phylogeographic structure and deep lineage diversification of the red alga Chondrus ocellatus Holmes in the Northwest Pacific
- DOI:
doi: 10.1111/mec.13367 - 发表时间:
2015 - 期刊:
- 影响因子:
- 作者:
Hu Zi-Min;Li Jing-Jing;Sun Zhong-Min;Oak Jung-Hyun;Zhang Jie;Fresia Pablo;Grant Stewart;Duan De-Lin - 通讯作者:
Duan De-Lin
MP73-07 PREDICTION OF LYMPH NODE INVASION IN PATIENTS WITH RENAL CELL CARCINOMA: RESULTS FROM A LARGE INTERNATIONAL CONSORTIUM
- DOI:
10.1016/j.juro.2016.02.1662 - 发表时间:
2016-04-01 - 期刊:
- 影响因子:
- 作者:
Paolo Dell'Oglio;Grant Stewart;Tobias Klatte;Alessandro Volpe;Bulent Akdogan;Marco Roscigno;Hans Langenhuijsen;Martin Marszalek;Oscar Rodriguez Faba;Maciej Salagierski;Andrea Minervini;Sabine Brookman-May;Umberto Capitanio - 通讯作者:
Umberto Capitanio
Grant Stewart的其他文献
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{{ truncateString('Grant Stewart', 18)}}的其他基金
Investigating the role of arginine methylation as a critical regulator of DNA replication and genome stability
研究精氨酸甲基化作为 DNA 复制和基因组稳定性关键调节因子的作用
- 批准号:
MR/W001152/1 - 财政年份:2022
- 资助金额:
$ 44.31万 - 项目类别:
Research Grant
Investigating the role of HNRPUL1 in regulating the ATR-dependent DNA damage response
研究 HNRPUL1 在调节 ATR 依赖性 DNA 损伤反应中的作用
- 批准号:
G0900088/1 - 财政年份:2009
- 资助金额:
$ 44.31万 - 项目类别:
Research Grant
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