2026年1月28日出版的《自然》杂志发表了南丹麦大学Kumar Somyajit小组的最新成果，他们的最新研究提出了PAF15-PCNA耗尽控制着DNA复制的链特异性控制。

本研究表明，过多的起始点激发会使染色质结合的增殖细胞核抗原（PCNA）饱和——这是DNA聚合酶活性和冈崎片段加工的滑动钳——从而在失去检查点控制时限制PCNA的进一步装载和滞后链合成。PCNA相关因子15（PAF15）作为该过程的剂量敏感调节剂出现。在无扰动S在这个阶段，整个可溶的PAF15池与染色质结合，在过度的起始活化条件下没有留下稳定PCNA的储备。PAF15通过一个高亲和力的PIP基序特异性地与滞后链上的PCNA结合，并占据DNA环绕通道，保护钳和相关酶免受ATAD5-RFC复合物的过早卸载。

相反，PAF15的过表达或强制重新分配到前导链会破坏复制体的进展并诱导细胞死亡。这些有害的影响可以通过阻断PAF15-PCNA在前导链上结合的Timeless-Claspin来减轻。E2F4介导的抑制微调PAF15的表达，以确保最佳的剂量和链特异性。这些发现揭示了以前未被认识到的复制体约束：当PAF15-PCNA组装耗尽时，S期检查点全局限制起源激活，将链特异性速率限制机制与全局复制动力学联系起来。

据介绍，真核生物基因组复制通过S期检查点进行调查，S期检查点协调顺序起源激活，以防止定义不清、限速的复制体成分耗尽。

附：英文原文

Title: PAF15–PCNA exhaustion governs the strand-specific control of DNA replication

Author: Chhetri, Gita, Badugu, Sugith Babu, Petriman, Narcis-Adrian, Petersen, Mikkel Bo, Gller, Aylin Seren, Fajri, Nora, Coule, Manon, Pitchai, Ganesha Pandian, Novotn, Jan, Larsen, Frederik Tibert, Mller, Andreas Fnss, Ebbesen, Morten Frend, Ravnsborg, Tina, Yadav, Anoop Kumar, Balarasa, Barath, Lunding, Anita, Polasek-Sedlackova, Hana, Jensen, Ole N., Ravnskjaer, Kim, Brewer, Jonathan R., Madsen, Jesper Grud Skat, Petryk, Nataliya, Andersen, Jens S., Somyajit, Kumar

Issue&Volume: 2026-01-28

Abstract: Eukaryotic genome replication is surveyed by the S-phase checkpoint, which coordinates sequential origin activation to prevent the exhaustion of poorly defined, rate-limiting replisome components1,2,3. Here we show that excessive origin firing saturates chromatin-bound proliferating cell nuclear antigen (PCNA)—a sliding clamp for DNA polymerase processivity and Okazaki fragment processing4—thereby restricting further PCNA loading and lagging-strand synthesis when checkpoint control is lost. PCNA-associated factor15 (PAF15) emerges as a dosage-sensitive regulator of this process5,6,7,8,9. During unperturbed Sphase, the entire soluble PAF15 pool binds to chromatin, leaving no reserve to stabilize PCNA under conditions of excessive origin activation. PAF15 binds to PCNA specifically on the lagging strand through a high-affinity PIP motif and occupies the DNA-encircling channel, protecting the clamp and associated enzymes from premature unloading by the ATAD5–RFC complex. Conversely, overexpression of PAF15 or forced redistribution to the leading strand disrupts replisome progression and induces cell death. These detrimental effects are mitigated by Timeless–Claspin, which blocks PAF15–PCNA binding on the leading strand. E2F4-mediated repression fine-tunes PAF15 expression to ensure optimal dosage and strand specificity. These findings reveal a previously unrecognized replisome constraint: when PAF15–PCNA assemblies are exhausted, the S-phase checkpoint globally restricts origin activation, linking a strand-specific rate-limiting mechanism to global replication dynamics.

DOI: 10.1038/s41586-025-10011-3

Source: https://www.nature.com/articles/s41586-025-10011-3