Compared to cells lacking Vpr (left), the cohesin Rad21 (red) is prematurely lost
from centromeres (arrowheads) in the presence of Vpr (right).
An HIV-1 protein promotes chromosome missegregation by epigenetically modifying centromeric
chromatin, Shimura et al. report.
Lymphocytes infected with HIV-1 display premature chromatid separation (PCS), in which
sister chromatids come apart too early in mitosis, increasing the possibility of missegregation
into the wrong daughter cell. This genomic instability may explain the increased incidences
of certain cancers in HIV-1 patients, though how HIV-1 induces PCS is unknown.
Shimura et al. found that viruses lacking the small accessory gene vpr didn't disrupt
chromatid cohesion, whereas expression of Vpr alone was sufficient to induce PCS.
Cohesin proteins, which link sister chromatids together until anaphase, were prematurely
lost from the centromeres of mitotic chromosomes, probably because hSgo1, a protein
that protects cohesins from dissociation, was displaced in the presence of Vpr.
hSgo1 is recruited to centromeres by heterochromatin proteins of the HP1 family. Shimura
et al. saw that HP1-α and HP1-γ were displaced from centromeric chromatin by Vpr and
that depleting HP1 proteins by RNAi caused similar levels of PCS. Vpr localized to
chromosomes—especially at centromeres—and displaced HP1-α and -γ by recruiting the
histone acetyltransferase p300 to modify the surrounding chromatin. Depleting or inhibiting
p300 prevented Vpr from displacing HP1 proteins and inducing PCS.
Blocking the interaction between Vpr and p300 may therefore reduce genomic instability
in long-term HIV-1 patients. Senior author Mari Shimura now wants to investigate how
the Vpr protein localizes to host cell chromosomes.