Virus infection necessarily requires redirecting cellular resources towards viral progeny production. Adenovirus successfully accomplishes this by usurping host chromatin through multiple approaches from redistributing histone modifications to globally altering chromatin composition. We previously showed that adenovirus histone-like protein VII sequesters the histone chaperone SET and the HMGB family of alarmins in host chromatin. HMGB1 has been shown to antagonize linker histone H1 binding to chromatin. Consistent with this antagonism, we find several H1 isoforms significantly chromatin-depleted in the presence of protein VII and accompanying HMGB proteins. Here, we use complementary systems in Saccharomyces cerevisiae and human cells to dissect the mechanism of chromatin invasion by adenovirus protein VII. In yeast, we find that protein VII binds chromatin and subsequently slows cell growth. Using yeast genetics, we demonstrate that loss of HMGB1 or SET homologs rescues this growth defect, indicating that these factors are required for the phenotype, while deletion of the linker histone H1 homolog exacerbates the defect. Strikingly, expression of human SET or HMGB1 in the corresponding mutant background restores the defects. We find that as a consequence of chromatin invasion, protein VII disrupts cell cycle progression such that cells accumulate in G2/M, both in yeast and diploid human cells. Moreover, we demonstrate that protein VII can impede the cell cycle in the presence of adenovirus E1A and E1B, two viral proteins well-established to override cell cycle checkpoints. Together, our results demonstrate that protein VII exploits H1-HMGB1 antagonism to invade chromatin and obstruct cell cycle progression, ensuring cellular resources are directed towards viral progeny production.
Linker histone H1 is present in centromeric chromatin of living human cells next to inner kinetochore proteins
