Powerful CRISPR cousin accidentally mutates RNA while editing DNA target

first_img Powerful CRISPR cousin accidentally mutates RNA while editing DNA target Country * Afghanistan Aland Islands Albania Algeria Andorra Angola Anguilla Antarctica Antigua and Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia, Plurinational State of Bonaire, Sint Eustatius and Saba Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory Brunei Darussalam Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos (Keeling) Islands Colombia Comoros Congo Congo, the Democratic Republic of the Cook Islands Costa Rica Cote d’Ivoire Croatia Cuba Curaçao Cyprus Czech Republic Denmark Djibouti Dominica Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands (Malvinas) Faroe Islands Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Gambia Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guatemala Guernsey Guinea Guinea-Bissau Guyana Haiti Heard Island and McDonald Islands Holy See (Vatican City State) Honduras Hungary Iceland India Indonesia Iran, Islamic Republic of Iraq Ireland Isle of Man Israel Italy Jamaica Japan Jersey Jordan Kazakhstan Kenya Kiribati Korea, Democratic People’s Republic of Korea, Republic of Kuwait Kyrgyzstan Lao People’s Democratic Republic Latvia Lebanon Lesotho Liberia Libyan Arab Jamahiriya Liechtenstein Lithuania Luxembourg Macao Macedonia, the former Yugoslav Republic of Madagascar Malawi Malaysia Maldives Mali Malta Martinique Mauritania Mauritius Mayotte Mexico Moldova, Republic of Monaco Mongolia Montenegro Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island Norway Oman Pakistan Palestine Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Poland Portugal Qatar Reunion Romania Russian Federation Rwanda Saint Barthélemy Saint Helena, Ascension and Tristan da Cunha Saint Kitts and Nevis Saint Lucia Saint Martin (French part) Saint Pierre and Miquelon Saint Vincent and the Grenadines Samoa San Marino Sao Tome and Principe Saudi Arabia Senegal Serbia Seychelles Sierra Leone Singapore Sint Maarten (Dutch part) Slovakia Slovenia Solomon Islands Somalia South Africa South Georgia and the South Sandwich Islands South Sudan Spain Sri Lanka Sudan Suriname Svalbard and Jan Mayen Swaziland Sweden Switzerland Syrian Arab Republic Taiwan Tajikistan Tanzania, United Republic of Thailand Timor-Leste Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks and Caicos Islands Tuvalu Uganda Ukraine United Arab Emirates United Kingdom United States Uruguay Uzbekistan Vanuatu Venezuela, Bolivarian Republic of Vietnam Virgin Islands, British Wallis and Futuna Western Sahara Yemen Zambia Zimbabwe Click to view the privacy policy. Required fields are indicated by an asterisk (*) Joung, a pioneering developer of base editors, was startled by the RNA changes, which had cytosines being converted to uracil, an RNA base that’s related to thymine. “When a postdoc first showed me the results and we saw tens of thousands of RNA cytosines being edited, I was like, ‘Wait a minute, what are we looking at here?’”Jia Chen, who does genome editing research at ShanghaiTech University in China and was not involved in the new work, was not as surprised, noting that deaminases were originally described as having the ability to alter RNA. But he says the new work will push the field to solve the problem. “The finding will [lead to] developing novel base editors with higher editing precision,” Chen says.Joung says his lab’s recent discovery of the old deaminase literature is what led his lab to do these experiments. And they’ve already engineered deaminases that substantially reduce the number of inadvertent RNA edits. “That was very encouraging to us,” Joung says. “We’re ultimately protein engineers, and we want to figure out if we can engineer the system to make the mutations go away.”David Liu, a Harvard University chemist who created the first base editor and co-founded two companies based on the technology with Joung, notes that deaminases naturally edit cellular RNA, stressing that the biological consequences of such editing are unclear. He adds that his own lab’s studies of base editors have also found RNA off-target edits, but at far lower levels. The differences between their results, says Liu, likely have less to do with the amount of off-target RNA editing that takes place than the different way Joung’s group sorted its cells and analyzed the results.Both Liu and Joung stress that their labs have found deaminases that work only on either DNA or RNA, which makes them confident that they can decouple the off-target effects seen with the current base editors. “Base editors are still incredibly powerful tools,” Joung says. “This is just another parameter we need to understand.” Sign up for our daily newsletter Get more great content like this delivered right to you! Country Emailcenter_img By Jon CohenApr. 17, 2019 , 4:10 PM The enzyme that gives a powerful tool known as a “base editor” the ability to change DNA also has an off-target effect on RNA (above). When researchers first reported 3 years ago that they had created base editors, a version of the powerful genome-editing tool CRISPR, excitement swirled around their distinct powers to more subtly alter DNA compared with CRISPR itself. But the weaknesses of base editors have become increasingly apparent, and a new study shows they can also accidentally mutate the strands of RNA that help build proteins or perform other key cellular tasks. Researchers say this could complicate developing safe therapies with the technology and hamper other research applications.Human diseases from sickle cell to Tay-Sachs are caused by a single mutation to one of the four DNA bases—adenine, guanine, cytosine, and thymine—and CRISPR has often had difficulty swapping out the bad actors. That’s in part because CRISPR cuts double-stranded DNA at targeted places and then relies on finicky cell repair mechanisms to do the heavy lifting of inserting a corrected DNA sequence for a mutation. Base editors, in contrast, chemically change one DNA base into another with enzymes called deaminases, which doesn’t require a cut or help from the cell.Base editors, which adapt key components of CRISPR to reach targeted places in the genome, have been shown to have many off-target effects on DNA. But until now, its effects on RNA, which contains three of the same bases as DNA, had escaped scrutiny. So J. Keith Joung, a pathologist and molecular biologist at the Massachusetts General Hospital in Boston, led a team that put base editors into human liver and kidney cells. Their finding: Deaminases can also alter RNA, the group reports today in Nature. nobeastsofierce Science/Alamy Stock Photo last_img