Lagadec Floriane, Singh Parmit K, Calmels Christina, Lapaillerie Delphine, Lindemann Dirk, Parissi Vincent, Cherepanov Peter, Engelman Alan N, Lesbats Paul
Fundamental Microbiology and Pathogenicity Lab (MFP), UMR 5234 CNRS-University of Bordeaux, SBM Department, F-33076 Bordeaux, France.
Viral DNA Integration and Chromatin Dynamics Network (DyNAVir), F-33076 Bordeaux, France.
Nucleic Acids Res. 2025 May 22;53(10). doi: 10.1093/nar/gkaf449.
Selection of a suitable chromatin environment during retroviral integration is a tightly regulated process. Most retroviruses, including spumaretroviruses, require mitosis for nuclear entry. However, whether intrinsic chromatin dynamics during mitosis modulates retroviral genome invasion is unknown. Previous work uncovered critical interactions of prototype foamy virus (PFV) Gag with nucleosomes via a highly conserved arginine anchor residue. Yet, the regulation of Gag-chromatin interaction and its functional consequences for spumaretrovirus biology remain obscure. Here, we investigated the kinetics of chromatin binding by Gag during mitosis and proviral integration in synchronized cells. We showed that alteration of Gag affinity for nucleosome binding induced untimely chromatin tethering during mitosis, decreased infectivity, and redistributed viral integration sites to markers associated with late replication timing of chromosomes. Mutant Gag proteins were, moreover, defective in their ability to displace the histone H4 tail from the nucleosome acidic patch of highly condensed chromatin. These data indicate that the chromatin landscape during Gag-nucleosome interactions is important for PFV integration site selection and that spumaretroviruses evolved high-affinity chromatin binding to overcome early mitosis chromatin condensation.
逆转录病毒整合过程中合适染色质环境的选择是一个受到严格调控的过程。大多数逆转录病毒，包括泡沫逆转录病毒，需要有丝分裂才能进入细胞核。然而，有丝分裂期间内在的染色质动态变化是否会调节逆转录病毒基因组的侵入尚不清楚。先前的研究发现原型泡沫病毒（PFV）的Gag通过一个高度保守的精氨酸锚定残基与核小体发生关键相互作用。然而，Gag-染色质相互作用的调控及其对泡沫逆转录病毒生物学的功能影响仍不清楚。在这里，我们研究了有丝分裂期间Gag与染色质结合的动力学以及同步化细胞中的前病毒整合。我们发现，Gag对核小体结合亲和力的改变会在有丝分裂期间导致染色质过早拴系，降低感染性，并将病毒整合位点重新分布到与染色体后期复制时间相关的标记上。此外，突变的Gag蛋白在从高度浓缩染色质的核小体酸性补丁中置换组蛋白H4尾巴的能力上存在缺陷。这些数据表明，Gag-核小体相互作用期间的染色质景观对PFV整合位点的选择很重要，并且泡沫逆转录病毒进化出高亲和力的染色质结合以克服有丝分裂早期的染色质凝聚。
