Lecture 16 - Human Papillomavirus (gene expression)

What does P(early) promoter express?

E1, E2, E6, and E7 in basal epithelial cells.

What does P(late) promoter express?

E1, E2, E4, E5, L1, and L2 in differentiated epithelial cells.

What is the function of the LCR (Long Control Region)?

It contains enhancers and transcription control elements; regulates replication and transcription.

What does E1 do?

Acts as a DNA helicase that binds the origin of replication and recruits host DNA replication machinery.

What does E2 do?

Regulates transcription, DNA replication, and genome maintenance.

How does E2 contribute to genome maintenance?

Tethers viral genome to host chromosomes during mitosis.

What is vegetative replication?

A burst of viral DNA replication in terminally differentiated epithelial cells for virion production.

Why is HPV replication in differentiated cells challenging?

Differentiated cells don't divide and lack DNA replication machinery.

How do small DNA viruses overcome the replication barrier in differentiated cells?

By encoding oncogenes E6 and E7

What is the role of E7 in oncogenesis?

Disrupts the Rb-E2F checkpoint, pushing cells into S-phase.

How does E7 lead to uncontrolled cell proliferation?

Binds and degrades Rb protein, freeing E2F to promote uncontrolled DNA synthesis.

What does E6 target and degrade?

p53 tumor suppressor protein.

What additional function does E6 have?

Activates telomerase, promoting cell immortalization.

How do E6 and E7 cooperate in oncogenesis?

E7 drives proliferation; E6 prevents apoptosis.

What triggers increased expression of L1 and L2?

Differentiation and suppression of the early polyadenylation site.

When are L1 and L2 proteins made?

Late in infection, after vegetative DNA replication.

Where does virion assembly occur?

In the nucleus of differentiated epithelial cells.

How are virions released from the body?

Through desquamation of cornified cells and shed of those cells with HPV with them

What does E4 do during viral release?

Disrupts cytokeratins to facilitate viral shedding.

What can happen following immune regression?

HPV DNA may remain in the basal epithelium and can be reactivated when immune surveillance wanes

What is a key step in cancer development from HPV?

Integration of HPV DNA into host genome.

What genes may be expressed during latency?

E1 and E2.

How does integration promote cancer?

Disrupts E2, increasing E6/E7 expression, leading to genomic instability.

What is required for full cellular transformation and immortalization?

Additional mutations, such as in Ras oncogene or UV damage, beyond E6/E7 expression.

What abilities do transformed cells have?

They have additional growth properties, including the ability to form tumours.