Epigenetic control of Microhomology Mediated End Joining (MMEJ) in heterochromatin of Lamina Associated Domains.

细胞每天遭受数以万计的DNA损伤，这需要快速和高保真的修复，以避免有害的基因突变和基因组重排。这种基因畸变会使基因表达失控，导致癌症等疾病。自从发现DNA是一种不稳定的分子以来，模式生物的遗传筛选和详细的生化分析已经剖析了修复DNA断裂的主要途径。尽管在确定DDR和DNA修复的关键因子方面取得了很大进展，但它们在核空间中的作用尚不清楚。哺乳动物细胞核的一个关键特征是基因组的非随机排列。染色体被限制在离散的区域内，在这些区域内，染色质被施加了进一步的空间组织水平。我们最近的数据表明，DNA修复效率和途径特异性在细胞核中并不相同，这与最近的结果一致，表明差异DNA修复是整个基因组突变变异的原因。更具体地说，我们发现与细胞核外围相关的基因组部分的DNA损伤利用错误的DNA修复以牺牲无错误。在不同的基因组位置，易出错或无错误通路的差异使用是否是基因组周围突变和基因组畸变变异的原因，以及这是否与基因组区域易位的倾向有关，目前还不清楚。该项目旨在破译这一现象背后的机制以及对基因组完整性和核功能的影响。我们在这里讨论的问题对人类健康具有重要意义，因为这种高度复杂的相互作用网络的调节异常可能导致遗传疾病和/或癌症。例如，在化疗或放疗后，癌症患者往往会在以后的生活中复发继发性肿瘤。更深入地了解三维基因组组织在调节DNA修复效率和途径选择中的作用，将揭示基因组中易受基因组不稳定影响的区域，并帮助我们理解为什么某些突变和易位在癌症中复发。因此，这个项目非常及时，将为DNA修复的区隔化提供开创性的见解，这是我们了解核结构如何影响基因组稳定性的知识中一个很大程度上未解决但非常重要的空白。

Cells are subjected to tens of thousands of DNA lesions a day, which require both rapid and high-fidelity repair to avoid deleterious genetic mutations and genomic rearrangements. Such genetic aberrations can deregulate gene expression and lead to diseases such as cancer. Since the discovery that the DNA is an unstable molecule, genetic screens in model organisms and detailed biochemical analyses have dissected the main pathways that repair DNA breaks. Although, there has been much progress in identifying key factors of DDR and DNA repair, it is not understood how they function in the nuclear space. A key feature of the mammalian cell nucleus is the non-random arrangement of the genome. Chromosomes are confined in discrete territories and within them further levels of spatial organisation are imposed on the chromatin. Our recent data show that DNA repair efficiency and pathway specificity is not the same everywhere in the nucleus and are in line with recent results that suggest that differential DNA repair is the cause of mutation variation across the genome. More specifically we find that DNA lesions in parts of the genome which associate with the periphery of the nucleus utilise erroneous DNA Repair in expense of error free. Whether the differential usage of error prone or error free pathways in different genomic locations is cause of mutation and genomic aberration variation around the genome and whether this is linked to the propensity of genomic regions to translocate is not at all clear. This projects aims to decipher the mechanism behind this phenomenon and the consequences for genome integrity and nuclear function. The questions we address here are of significant importance for human health because abnormalities in the regulation of this highly complex network of interactions can give rise to genetic diseases and/or cancer. For example after chemotherapy or radiotherapy, cancer patients often develop recurrent secondary tumors later in life. Greater knowledge of the role of 3D genome organization in regulating DNA repair efficiency and pathway choice will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancers. Therefore, this project is very timely and will give groundbreaking insight into the compartmentalization of DNA repair, a largely unaddressed but very important gap in our knowledge to understand how nuclear architecture impinges on genome stability.