A viral histone-like protein exploits antagonism between linker histones and HMGB proteins to obstruct the cell cycle

Virus infection necessarily requires redirecting cellular resources toward viral progeny production. Adenovirus encodes the histone-like protein VII, which causes catastrophic global reorganization of host chromatin to promote virus infection. Protein VII recruits the family of high mobility group box (HMGB) proteins to chromatin along with the histone chaperone SET. As a consequence of this recruitment, we find that protein VII causes chromatin depletion of several linker histone H1 isoforms. The relationship between linker histone H1 and the functionally opposite HMGB proteins is critical for higher-order chromatin structure. However, the physiological consequences of perturbing this relationship are largely unknown. Here, we employ complementary systems in Saccharomyces cerevisiae and human cells to demonstrate that adenovirus protein VII disrupts the H1-HMGB balance to obstruct the cell cycle. We find that protein VII causes an accumulation of G2/M cells both in yeast and human systems, underscoring the high conservation of this chromatin vulnerability. In contrast, adenovirus E1A and E1B proteins are well established to override cell cycle regulation and promote transformation of human cells. Strikingly, we find that protein VII obstructs the cell cycle, even in the presence of E1A and E1B. We further show that, in a protein-VII-deleted infection, several cell cycle markers are regulated differently compared to wild-type infection, supporting our model that protein VII plays an integral role in hijacking cell cycle regulation during infection. Together, our results demonstrate that protein VII targets H1-HMGB1 antagonism to obstruct cell cycle progression, revealing an unexpected chromatin vulnerability exploited for viral benefit. [Display omitted] •Protein VII causes cell cycle delays by interacting directly with chromatin•HMGB1 and SET promote protein VII’s impact on chromatin•Linker histones protect chromatin from protein VII’s effects•Protein VII contributes to cell cycle hijacking by adenovirus during infection Lynch et al. define a novel mechanism of chromatin disruption caused by adenovirus protein VII. Using complementary systems in budding yeast and human cells, they show that protein VII disrupts the balance between linker histones and high mobility group box proteins. This blocks cell cycle progression, which ultimately promotes infection.