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Global Translational Medicine The research advances in HPV integration

suggested that HPV initially integrates into the host cell lines. Their hypothesis posits that HPV integrants
genome at random sites based on genome accessibility. bridge discontinuous host sequences by connecting nicked
However, over the course of extended carcinogenesis, there sites. This connection leads to a focused amplification of
appears to be a propensity for integration to concentrate breakpoints, including viral and flanking host sequences.
at specific loci, at which recurrent observations of Such amplification occurs through the replication of
integration have been made. This phenomenon may transient circular structures and circularized genomic
confer selective advantages to host cells, resulting in the segments. The subsequent recombination of distal free
formation of integration hotspots in different samples . ends with noncontiguous sequences, coupled with repair
[17]
Several possible mechanisms have been proposed to processes, further explains the tandem insertion of HPV
elucidate HPV integration, including a DNA damage fragments. This tandem insertion exhibits one identical
response, a looping model, and microhomology-mediated breakpoint shared across multiple fragments, while unique
integration. Importantly, multiple integration mechanisms breakpoints manifest on the opposite side.
may concurrently operate. The following sections briefly
introduce the principal mechanisms of integration that 2.3. Microhomology-mediated integration
have been proposed. Zones of microhomology (MH) with a maximum length
of 4 bp between the viral genome and the host genome can
2.1. DNA damage response be detected in proximity to the integration sites. Initially,
The frequency of integration is thought to be related to it was suggested that homologous stretches of DNA
the degree of DNA damage, as the integration process facilitate the annealing of partially dissociated strands,
necessitates the creation of double-strand breaks in both thereby facilitating recombination. Importantly, sequence
the viral and host DNA . Notably, several proteins pivotal homology at the integration site was posited as not strictly
[18]
[27]
[26]
in DNA double-strand break repair pathways exhibit necessary . Two probable mechanisms, FoSTeS
significant upregulation in various tumors. The integration (fork stalling and template switching) and MMBIR
into related genes further facilitates the insertion of the viral (microhomology-mediated break-induced replication),
genome [19,20] . HPV infection and genome replication within have been identified in this context. Both mechanisms
cells induce the recruitment of excessive DNA damage are triggered by local genomic instability and integration
factors, creating favorable conditions for the accidental sites have been significantly enriched in several genomic
integration of viral DNA . Chromatin enriched in E2 and instability-related elements, such as satellite and short
[21]
[17]
Brd4 is frequently situated proximal to common fragile interspersed nuclear element (SINE)-Alu repeats . These
sites and nucleic acid replication foci. This observation findings suggest that HPV might leverage the zones of MH
supports the theory that HPV exploits the host DNA repair flanking the breakpoint to hijack the DNA repair pathway
mechanism, thus promoting its own replication . Beyond as a means of inserting the viral genome into the damaged
[22]
its role in viral replication, E1 has been found to suppress host genome.
the growth of host cells through a mechanism associated
with the activation of DNA damage responses . 3. The role of HPV in cellular transformation
[23]
Consequently, E1 expression is hypothesized to promote and carcinogenesis
HPV integration, with its interruption during integration Integration alone proves insufficient to affect terminal
resulting in the loss of the growth-suppressing properties cell differentiation or induce malignant transformation;
associated with the E1 protein. Moreover, HPV16 E6*, the additional alterations to host-cell genes and accompanying
spliced isoform of E6, has been shown to elevate levels of epigenetic modifications are required for tumorigenesis .
[28]
reactive oxygen species, inducing chronic oxidative stress In the context of HPV-positive primary tumors, numerous
and cellular DNA damage. This process, in turn, increases structural variants and expression patterns, along with
the frequency of HPV integration, a relationship confirmed differential DNA methylation, have been associated with
in both oral and cervical keratinocytes . viral integration. Notably, many of these changes are
[24]
shared between head-and-neck squamous cell carcinomas
2.2. Looping model (HNSCC) and CC [13,19,29] . Earlier studies characterized viral
In this model, HPV integration is mediated through integration patterns as Type I (a single integrated copy)
DNA replication and recombination, providing insight or Type II (multiple tandem head-to-tail repeats of the
into the structural aspects of HPV insertions flanked by viral genome). Recent studies, however, have confirmed
host copy-number variations. Akagi et al. observed a that host-cell flanking sequences are often coamplified
[25]
recurrent pattern of focal amplification and rearrangement and rearranged. They have introduced a third integration
adjacent to HPV integration sites in HPV-positive cancer type (Type III), where tandem copies of the HPV

Volume 2 Issue 4 (2023) 3 https://doi.org/10.36922/gtm.2034