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<p>Melanin pigments block genotoxic agents by positioning on the sun-exposed side of the nucleus in human skin keratinocytes. How this positioning is regulated and its role in genome photoprotection remain unknown. Here, by developing a model of human keratinocytes internalizing extracellular melanin into pigment organelles, we show that keratin 5 and keratin 14 intermediate filaments and microtubules control the three-dimensional perinuclear position of pigments, shielding DNA from photodamage. Imaging and microrheology in a human-disease-related model identify structural keratin cages surrounding pigment organelles to stiffen their microenvironment and maintain their three-dimensional position. Optimum supranuclear spatialization of pigment organelles is required for DNA photoprotection and relies on intermediate filaments and microtubules bridged by plectin cytolinkers. Thus, the mechanically driven proximity of pigment organelles to the nucleus is a key photoprotective parameter. Uncovering how human skin counteracts solar radiation by positioning the melanin microparasol next to the genome anticipates that dynamic spatialization of organelles is a physiological response to ultraviolet stress.</p>

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Keratin intermediate filaments mechanically position melanin pigments for genome photoprotection

  • 期刊论文

  • 发表日期：

    2025年12月15日

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  • Silvia Benito-Martínez,
  • Laura Salavessa,
  • Anne-Sophie Macé,
  • Myckaëla Rouabah,
  • Nathan Lardier,
  • Vincent Fraisier,
  • Julia Sirés-Campos,
  • Riddhi Atul Jani,
  • Maryse Romao,
  • Vanessa Roca,
  • Charlène Gayrard,
  • Marion Plessis,
  • Ilse Hurbain,
  • Cécile Nait-Meddour,
  • Sandrine Etienne-Manneville,
  • Etienne Morel,
  • Michele Boniotto,
  • Jean-Baptiste Manneville,
  • Françoise Bernerd,
  • Christine Duval,
  • Graça Raposo,
  • Cédric Delevoye

摘要

Melanin pigments block genotoxic agents by positioning on the sun-exposed side of the nucleus in human skin keratinocytes. How this positioning is regulated and its role in genome photoprotection remain unknown. Here, by developing a model of human keratinocytes internalizing extracellular melanin into pigment organelles, we show that keratin 5 and keratin 14 intermediate filaments and microtubules control the three-dimensional perinuclear position of pigments, shielding DNA from photodamage. Imaging and microrheology in a human-disease-related model identify structural keratin cages surrounding pigment organelles to stiffen their microenvironment and maintain their three-dimensional position. Optimum supranuclear spatialization of pigment organelles is required for DNA photoprotection and relies on intermediate filaments and microtubules bridged by plectin cytolinkers. Thus, the mechanically driven proximity of pigment organelles to the nucleus is a key photoprotective parameter. Uncovering how human skin counteracts solar radiation by positioning the melanin microparasol next to the genome anticipates that dynamic spatialization of organelles is a physiological response to ultraviolet stress.