4.5 Article

RPA facilitates rescue of keratinocytes from UVB radiation damage through insulin-like growth factor-I signalling

Journal

JOURNAL OF CELL SCIENCE
Volume 134, Issue 12, Pages -

Publisher

COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.255786

Keywords

Keratinocyte; Ultraviolet radiation; DNA damage; Insulin-like growth factor; Skin models; Photodamage repair

Categories

Funding

  1. Manipal Academy of Higher Education (MAHE), India
  2. Queensland University of Technology (QUT), Australia
  3. Dr. TMA Pai PhD Scholarship
  4. MAHE
  5. QUT Postgraduate Research Award
  6. UT HDR Tuition Fee Sponsorship, QUT

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UVBR-induced DNA photolesions impair keratinocyte functions and determine cell fate, while IGF-I can rescue keratinocytes by preventing apoptosis and removing photolesions. The study on the impact of signalling inhibitors revealed the crucial role of RPA in linking damage response activation, cell cycle regulation, repair, and survival pathways initiated by IGF-I.
UVBR-induced photolesions in genomic DNA of keratinocytes impair cellular functions and potentially determine the cell fate post-irradiation. The ability of insulin-like growth factor-I (I GF-I) to rescue epidermal keratinocytes after photodamage via apoptosis prevention and photolesion removal was recently demonstrated using in vitro two-dimensional and three-dimensional skin models. Given the limited knowledge of specific signalling cascades contributing to post-UVBR IGF-I effects, we used inhibitors to investigate the impact of blockade of various signalling mediators on IGF-I photoprotection. IGF-I treatment, in the presence of signalling inhibitors, particularly TDRL-505, which targets replication protein A (RPA), impaired activation of IGF-1R downstream signalling, diminished cyclobutane pyrimidine dimer removal, arrested growth, reduced cell survival and increased apoptosis. Further, the transient partial knockdown of RPA was found to abrogate IGF-I-mediated responses in keratinocytes, ultimately affecting photoprotection and, thereby, establishing that RPA is required for IGF-I function. Our findings thus elucidate the importance of RPA in linking the damage response activation, cell cycle regulation, repair and survival pathways, separately initiated by IGF-I upon UVBR-induced damage. This information is potentially imperative for the development of effective sunburn and photodamage repair strategies. This article has an associated First Person interview with the first author of the paper.

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