ZNF280A将DNA双链断裂修复与人类22q11.2远端缺失综合征联系起来，这一成果由麻省总医院癌症中心Raul Mostoslavsky研究组经过不懈努力而取得。该项研究成果发表在2025年6月16日出版的《自然—生物细胞学》上。

利用高通量显微镜结合cDNA“chromORFeome”文库，该研究团队发现ZNF280A是一种未被表征的染色质因子，它被招募到断裂中，对DNA DSB修复至关重要。缺乏ZNF280A导致基因组不稳定和对DNA损伤剂的大量敏感性。在机制上，该课题组研究人员证明了ZNF280A通过促进BLM-DNA2解旋酶-核酸酶复合物在DNA DSB位点的募集，提高该复合物在DNA损伤位点的酶活性效率，从而促进远程DNA末端切除。因此，ZNF280A对于DNA末端切除和同源重组修复至关重要。重要的是，ZNF280A在人类遗传病22q11.2远端缺失综合征中半合子性缺失。这种疾病的特征包括先天性心脏病、小头畸形、免疫缺陷、发育迟缓和认知缺陷——这些特征与其他由参与DNA修复的基因缺陷引起的人类综合症有关。值得注意的是，具有22q11.2远端缺失的个体的细胞在dna末端切除和同源物重组方面存在缺陷，导致基因组不稳定性的发生率增加。通过重新引入ZNF280A，这些表型得以恢复，这为DNA修复缺陷作为与这种人类疾病相关的几种临床特征的潜在机制解释提供了证据。

据了解，DNA双链断裂（DSB）是DNA损伤中最有害的形式之一，如果不解决，会导致DNA突变和染色体畸变，从而导致包括癌症在内的疾病。通过同源体重组修复DSB需要在DNA末端广泛的解核消化过程中称为DNA末端切除。近年来，在了解这一过程是如何开始的方面取得了进展，但对这一过程的后期阶段还没有很好的了解。许多问题仍然存在，比如催化这一过程的DNA解旋酶和内切酶是如何被调节的，DNA双链断裂（DSB）是DNA损伤中最有害的形式之一，如果不解决，就会导致DNA突变和染色体畸变，从而导致包括癌症在内的疾病。通过同源体重组修复DSB需要在DNA末端广泛的解核消化过程中称为DNA末端切除。近年来，在理解这一过程是如何开始的方面取得了进展，但这一过程的后期阶段——远程DNA末端切除——还没有得到很好的理解。许多问题仍然存在于催化这一过程的DNA解旋酶和内切酶是如何被调节的，这是在没有断裂的情况下避免假体活性的关键一步。DNA末端切除在人类疾病中的重要性被一些人类遗传综合征所突出，这些遗传综合征是由参与这一过程的关键蛋白质的突变或缺陷引起的。

附：英文原文

Title: ZNF280A links DNA double-strand break repair to human 22q11.2 distal deletion syndrome

Author: Clarke, Thomas L., Cho, Hyo Min, Ceppi, Ilaria, Gao, Boya, Yadav, Tribhuwan, Silveira, Giorgia G., Boon, Ruben, Martinez-Pastor, Barbara, Amoh, Nana Yaa A., Machin, Belen, Bernasocchi, Tiziano, Ashfaq, Dua, Mendez, Josefina, Kamaliyan, Zeeba, Del Ro Pantoja, Jos, Rogines, Giuliana Sardi, Crowley, Blaine T., McGinn, Daniel E., Giunta, Victoria, Tran, Oanh, Zackai, Elaine H., Lan, Li, Zou, Lee, Emanuel, Beverly S., McDonald-McGinn, Donna M., Cejka, Petr, Mostoslavsky, Raul

Issue&Volume: 2025-06-16

Abstract: DNA double-strand breaks (DSB) are among the most deleterious forms of DNA damage and, if unresolved, result in DNA mutations and chromosomal aberrations that can cause disease, including cancer. Repair of DSBs by homologous recombination requires extensive nucleolytic digestion of DNA ends in a process known as DNA-end resection. In recent years, progress has been made in understanding how this process is initiated, but the later stages of this process—long-range DNA-end resection—are not well understood. Many questions remain in terms of how the DNA helicases and endonucleases that catalyse this process are regulated, a key step DNA double-strand breaks (DSB) are among the most deleterious forms of DNA damage and, if unresolved, result in DNA mutations and chromosomal aberrations that can cause disease, including cancer. Repair of DSBs by homologous recombination requires extensive nucleolytic digestion of DNA ends in a process known as DNA-end resection. In recent years, progress has been made in understanding how this process is initiated, but the later stages of this process—long-range DNA-end resection—are not well understood. Many questions remain in terms of how the DNA helicases and endonucleases that catalyse this process are regulated, a key step to avoiding spurious activity in the absence of breaks. The importance of DNA-end resection in human disease is highlighted by several human genetic syndromes that are caused by mutations or deficiencies in key proteins involved in this process. Here, using high-throughput microscopy coupled with a cDNA ‘chromORFeome’ library, we identified ZNF280A as an uncharacterized chromatin factor that is recruited to breaks and essential for DNA DSB repair. Lack of ZNF280A drives genomic instability and substantial sensitivity to DNA-damaging agents. Mechanistically, we demonstrate that ZNF280A promotes long-range DNA-end resection by facilitating the recruitment of the BLM–DNA2 helicase–nuclease complex to DNA DSB sites, enhancing efficiency of the enzymatic activity of this complex at DNA damage sites. ZNF280A is therefore essential for DNA-end resection and DNA repair by homologous recombination. Importantly, ZNF280A is hemizygously deleted in a human genetic condition, 22q11.2 distal deletion syndrome. Features of this condition include congenital heart disease, microcephaly, immune deficiency, developmental delay and cognitive deficits—features that are associated with other human syndromes caused by defects in genes involved in DNA repair. Remarkably, cells from individuals with a 22q11.2 distal deletion have defects in DNA-end resection and homologous recombination, resulting in increased incidence of genomic instability. These phenotypes are rescued by reintroduction of ZNF280A, providing evidence of defective DNA repair as a potential mechanistic explanation for several clinical features associated with this human condition.

DOI: 10.1038/s41556-025-01674-1

Source: https://www.nature.com/articles/s41556-025-01674-1