A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder.
A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder.
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DOI：
10.1016/j.jbc.2023.104656
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发表时间：
2023-05
影响因子：
4.8
通讯作者：
Kelch, Brian A.
中科院分区：
文献类型：
--
作者：
Magrino, Joseph;Munford, Veridiana;Martins, Davi Jardim;Homma, Thais K.;Page, Brendan;Gaubitz, Christl;Freire, Bruna L.;Lerario, Antonio M.;Vilar, Juliana Brandstetter;Amorin, Antonio;Leao, Emilia K. E.;Kok, Fernand;Menck, Carlos F. M.;Jorge, Alexander A. L.;Kelch, Brian A.
增殖细胞核抗原（PCNA）是一种滑动钳蛋白，协调DNA复制和各种DNA维持事件，对人类健康至关重要。最近，一种被称为pnas相关DNA修复障碍（PARD）的罕见DNA修复障碍在PCNA中被描述为异亮氨酸（S228I）的半胚纯合丝氨酸取代。PARD症状包括紫外线敏感、神经退行性变、毛细血管扩张和早衰。我们和其他人先前表明，S228I变体将PCNA的蛋白质结合袋改变为损害与特定伙伴相互作用的构象。在这里，我们报告了第二个PCNA替换（C148S）也会导致PARD。与PCNA-S228I不同，PCNA-C148S具有类似wt的结构和对伙伴的亲和力。相反，这两种疾病相关的变异都具有热稳定性缺陷。此外，C148S等位基因纯合的患者源性细胞表现出低水平的染色质结合PCNA，并表现出温度依赖性表型。两种PARD变体的稳定性缺陷表明PCNA水平可能是PARD疾病的重要驱动因素。这些结果极大地促进了我们对PARD的理解，并可能刺激更多的工作集中在这种严重疾病的临床、诊断和治疗方面。
Proliferating cell nuclear antigen (PCNA) is a sliding clamp protein that coordinates DNA replication with various DNA maintenance events that are critical for human health. Recently, a hypomorphic homozygous serine to isoleucine (S228I) substitution in PCNA was described to underlie a rare DNA repair disorder known as PCNA-associated DNA repair disorder (PARD). PARD symptoms range from UV sensitivity, neurodegeneration, telangiectasia, and premature aging. We, and others, previously showed that the S228I variant changes the protein-binding pocket of PCNA to a conformation that impairs interactions with specific partners. Here, we report a second PCNA substitution (C148S) that also causes PARD. Unlike PCNA-S228I, PCNA-C148S has WT-like structure and affinity toward partners. In contrast, both disease-associated variants possess a thermostability defect. Furthermore, patient-derived cells homozygous for the C148S allele exhibit low levels of chromatin-bound PCNA and display temperature-dependent phenotypes. The stability defect of both PARD variants indicates that PCNA levels are likely an important driver of PARD disease. These results significantly advance our understanding of PARD and will likely stimulate additional work focused on clinical, diagnostic, and therapeutic aspects of this severe disease.
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影响因子：
4.5
作者：
Hendel A;Krijger PH;Diamant N;Goren Z;Langerak P;Kim J;Reissner T;Lee KY;Geacintov NE;Carell T;Myung K;Tateishi S;D'Andrea A;Jacobs H;Livneh Z
通讯作者：
Livneh Z
影响因子：
3.8
作者：
Dieckman, Lynne M.;Washington, M. Todd
通讯作者：
Washington, M. Todd
影响因子：
15.9
作者：
Gineau, Laure;Cognet, Celine;Jouanguy, Emmanuelle
通讯作者：
Jouanguy, Emmanuelle
影响因子：
15.9
作者：
Hughes, Claire R.;Guasti, Leonardo;Metherell, Louise A.
通讯作者：
Metherell, Louise A.
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K